Carbapenem derivatives

ABSTRACT

A compound of the formula: ##STR1## wherein R 1  is a hydrogen atom or a lower alkyl group, R 2  is a hydrogen atom or a negative charge, R 3  is a hydrogen atom or a lower alkyl group, Ar is a phenyl group, a naphthyl group or a group of: ##STR2## (wherein each of A 4  and A 5  is a single bond, --NHSO 2  -- or the like, and Het is a pyrrolinyl group, a 1,4-diazabicyclo 2.2.2!octanyl group or the like which may be substituted with a hydroxyl group, a carbamoyl lower alkyl group or the like) which may be substituted with a lower alkyl group, a lower alkylsulfamoyl group or the like which may be substituted with a hydroxyl group, a di-lower alkylsulfonyl group or the like; a hydroxyl group; a di-lower alkylsulfamoyl group or the like, each of A 1 , A 2  and A 3  is a single bond or a lower alkylene group which may be substituted with a lower alkyl group, a lower alkylsulfamoyl group or the like which may be substituted with a hydroxyl group, a di-lower alkylsulfamoyl group or the like; a pyridyl group or a pyridino group; and W is a sulfur atom, a single bond; or a pharmaceutically acceptable salt or ester; a process for its production and an antibacterial agent containing it as an active ingredient.

TECHNICAL FIELD

This application is a 371 of PCT/JP95/00280 Feb. 24, 1995.

The present invention relates to novel carbapenem (7-oxo-1-azabicyclo3.2.0!hept-2-en-2-carboxylic acid) compounds, antibacterial agentscontaining such compounds as active ingredients, and a process forproducing such compounds.

BACKGROUND ART

In recent years, new β-lactam antibiotic substances have been found innature which have the same β-lactam rings as penicillin derivatives andas cephalosporin derivatives, but which have different basic structures.

For example, naturally derived carbapenem compounds such as thienamycinisolated from the fermentation of Streptomyces Cattleya (J. Am. Chem.Soc., vol. 100, p.6491 (1978)), may be mentioned. Thienamycin has anexcellent antibacterial spectrum and strong antibacterial activitiesover a wide range against gram positive bacteria and gram negativebacteria. Therefore, its development as a highly useful β-lactam agenthas been expected. However, thienamycin itself is chemically unstable,and it has been reported that it is likely to be decomposed by a certainenzyme in vivo such as renal dehydropeptidase I (hereinafter referred tosimply as DHP-I), whereby the antibacterial activities tend to decrease,and the recovery rate in the urine is low (Antimicrob. AgentsChemother., vol. 22, p.62 (1982); ditto, vol. 23, p.300 (1983)).

Merck & Co., Inc. have synthesized many thienamycin analogues with anaim to maintain the excellent antibacterial activities of thienamycinand to secure chemical stability. As a result, imipenem, (5R,6S)-3-2-(formimidoylamino)ethylthie!-6- (R)-1-hydroxyethyl!-7-oxo-1-azabicyclo3.2.0!hept-2-en-2-carboxylic acid monohydrate, obtained by formimidationof the amino group of thienamycin, has been practically developed as apharmaceutical product (J. Med. Chem., vol. 22, p. 1435 (1979)).

Imipenem has antibacterial activities of an equal or higher level thanthienamycin against various types of bacteria and has β-lactamaseresistance. Especially against Pseudomonas aeruginosa, its antibacterialactivities are superior to thienamycin by from 2 to 4 times. Further,the stability of imipenem in the solid form or in an aqueous solution isremarkably improved over thienamycin.

However, like thienamycin, imipenem is likely to be decomposed by DHP-Iin the human kidney. Therefore, it can not be used for treatment of theurinary-tract infection. Further, it presents toxicity against thekidney due to the decomposition products. Therefore, imipenem can not beadministered alone and is required to be used in combination with aDEP-I inhibitor like cilastatin (J. Antimicrob. Chemother., vol. 12(Suppl. D), p. 1 (1983)). In recent years, imipenem has been frequentlyused for the treatment and prevention of infectious diseases.Consequently, highly methicillin-resistant Staphylococcus aureus whichis resistant to imipenem and imipenem-resistant Pseudomonas aeruginosaare increasing in the clinical field. Imipenem does not show adequatetreating effects against these resistant bacteria.

As the prior arts closest to the present invention, Japanese UnexaminedPatent Publication No. 179876/1988 (hereinafter referred to aspublication A) and Japanese Unexamined Patent Publication No.204490/1990 (hereinafter referred to as publication B) may be mentioned.Publication A describes carbapenem compounds having at the 2-position ofthe carbapenem structure a pyrrolidinylthio group substituted with agroup of A--X--R⁴. Publication B describes carbapenem compounds havingat the 2-position of the carbapenem structure a pyrrolidinylthio groupsubstituted with a group of A--O--R⁴.

However, according to publication A, the definition of R⁴ in thesubstituent is restricted to an optionally substituted lower alkylgroup, a heterocyclic group which may be optionally substituted ora-lower alkylsulfonyl group. Similarly, publication B mentions that thedefinition of R⁴ in the substituent is restricted to a substituted loweralkyl group such as a monohalo(lower)alkyl group, a mono- ordi-(lower)alkylamino(lower)alkyl group, a protectedmono(lower)alkylamino(lower)alkyl group, a mono- ordi-(lower)alkylcarbamoyl(lower)alkyl group or a protected or unprotectedcarboxy(lower)alkyl group.

The above-mentioned publications A and B as the prior arts disclose asthe utility of their inventions that these compounds have antibacterialactivities, but present only data obtained by using Staphylococcusaureus and Pseudomonas aeruginosa as test bacteria.

Namely, these prior arts do not disclose or suggest the compounds of thepresent invention characterized by having a substituent presented by theformula: ##STR3## wherein R³ is a hydrogen atom or a lower alkyl group,Ar is a phenyl group, a naphthyl group or a group of: ##STR4## (whereineach of A₄ and A₅, which may be the same or different, is a single bond,a methylene group, an ethylene group, an oxygen atom, an imino group, asulfur atom, a sulfonyl group, --CONH-- or --NHSO₂ --, and Het is apyrrolinyl group, a pyrrolyl group, an imidazolyl group, an imidazoliogroup, a pyrazolyl group, a thiazolyl group, a pyridyl group, apyridinio group, a pyrazinyl group, a quinolyl group, an isoquinolylgroup, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, amorpholinyl group, a benzothiazolyl group, an isoindolyl group, aquinuclidinyl group, a quinuclidinio group, abenzothiazol-1,1-dioxo-6-yl group or a 1,4-diazabicyclo 2.2.2!octanylgroup which may be substituted with the same or different one to threesubstituents, selected from the group consisting of a hydroxyl group, ahalogen atom, a cyano group, a carboxyl group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a di-loweralkylcarbamoyl group, a carbamoyloxy group, an amino group, a loweralkylamino group, a di-lower alkylamino group, a tri-lower alkylammoniogroup, a formimidoylamino group, an acetimidoylamino group, a loweralkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, asulfo group, a sulfamoyl group, a lower alkylsulfamoyl group, a di-loweralkylsulfamoyl group, a lower alkyl group, a hydroxy lower alkyl groupand a carbamoyl lower alkyl group) which may be substituted with thesame or different one to five substituents selected from the groupconsisting of a lower alkyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a lower alkylamino group, a lower alkoxygroup, an aryloxy group, a lower alkylthio group, a lower alkylsulfonylgroup and a lower alkylsulfamoyl group which may be substituted with thesame or different one to three substituents selected from the groupconsisting of a hydroxyl group, a halogen atom, a cyano group, acarboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a loweralkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxygroup, an amino group, a lower alkylamino group, a di-lower alkylaminogroup, a tri-lower alkylammonio group, a carbamoyl lower alkylaminogroup, an aroylamino group, an amino lower alkyl group, an amino loweralkylcarbonylamino group, a pyridyl group, a pyridylcarbonylamino group,a pyridiniocarbonylamino group, a formimidoylamino group, anacetimidoylamino group, a lower alkoxy group, a lower alkylthio group, asulfo group, an aminosulfonyl group, a lower alkylsulfonyl group and adi-lower alkylsulfonyl group, and a hydroxyl group, a halogen atom, acyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoylgroup, a di-lower alkylcarbamoyl group, an arylcarbamoyl group, apiperazinocarbonyl group, an amino group, a di-lower alkylamino group, atri-lower alkylammonio group, a sulfamino group, a lower alkanoylaminogroup, an aralkylamino group, an aroylamino group, an arylsulfonylaminogroup, an amino lower alkylcarbonylamino group, a sulfamoyl group and adi-lower alkylsulfamoyl group, each of A₁, A₂ and A₃, which may be sameor different, is a single bond or a lower alkylene group which may besubstituted with a substituent selected from the group consisting of alower alkyl group, a lower alkylcarbamoyl group, a lower alkylaminogroup, a lower alkoxy group, a lower alkylthio group, a loweralkylsulfonyl group, a lower alkylsulfonylamino group and a loweralkylsulfamoyl group which may be substituted with the same or differentone to three substituents selected from the group consisting of ahydroxyl group, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino group, alower alkylamino group, a di-lower alkylamino group, a tri-loweralkylammonio group, a formimidoylamino group, an acetimidoylamino group,a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonylgroup, a sulfo group, a sulfamoyl group, a lower alkylsulfamoyl groupand a di-lower alkylsulfamoyl group, and a pyridyl group and a pyridiniogroup (wherein the pyridyl group and the pyridinio group may besubstituted with a substituent selected from the group consisting of alower alkyl group, a carboxy lower alkyl group and a carbamoyl loweralkyl group), and W is a sulfur atom, a group of N--X (wherein X is ahydrogen atom, a lower alkyl group, a formal group, a lower alkanoylgroup or a sulfamoyl group), an oxygen atom, a group of CH(OH) or asingle bond, much less the marked effects of the compounds onmethycillin resistant Staphylococcus aureus.

β-Lactam antibiotics exhibit selective toxicity against bacteria andshow no substantial effects against animal cells. Therefore, they arewidely used for treatment of infectious diseases caused by bacteria, asantibiotics having little side effects, and thus are highly usefuldrugs.

However, in recent years, methicillin-resistant Staphylococcus aureus(hereinafter referred to simply as MRSA), methicillin-resistantcoagulase negative Staphylococci (hereinafter referred to simply asMRCNS) and resistant Pseudomonas aeruginosa have been isolatedfrequently from patients with the immunity decreased, as bacteriacausing hardly curable infectious diseases, and are raising a seriessocial problem. Further, recently, the strong toxicity of vancomycin,which is selectively used against MRSA, to the kidney, and theincreasing resistance of pathogenic bacteria such as MRSA and MRCNS arebecoming clinically serious problems. Accordingly, it is stronglydesired to develop an antibacterial agent having excellent antibacterialactivities against such resistant bacteria. However, no β-lactamantibacterial agents which meet such desire have not been developed yet.With respect to carbapenem compounds, such drugs are strongly desired tobe developed as have improved antibacterial activities against bacteriacausing hardly curable infectious diseases, especially against MRSA andMRCNS, improved stability against DHP-I, reduced toxicity against thekidney and no side effects against the central nervous system.

DISCLOSURE OF INVENTION

The present inventors have made extensive researches with an aim toprovide novel carbapenem compounds which have excellent antibacterialactivities and which are resistant to DHP-I. As a result, they havefound that carbapenem compounds of the present invention having, at the2-position of the carbapenem structure, a group of the formula: ##STR5##wherein R³, Ar, A₁, A₂, A₃ and W are as defined above, are novelcompounds not disclosed in any literatures, and that such compounds havestrong antibacterial activities against gram positive bacteria includingMRSA and against gram negative bacteria including Pseudomonas aeruginosaand further exhibit excellent stability against DHP-I. The presentinvention has been accomplished on the basis of this discovery.

The present invention provides a compound of the formula: ##STR6##wherein R¹ is a hydrogen atom or a lower alkyl group, R² is a hydrogenatom or a negative charge, R³ is a hydrogen atom or a lower alkyl group,Ar is a phenyl group, a naphthyl group or a group of: ##STR7## (whereineach of A₄ and A₅, which may be the same or different, is a single bond,a methylene group, an ethylene group, an oxygen atom, an imino group, asulfur atom, a sulfonyl group, --CONH-- or --NHSO₂ --, and Het is apyrrolinyl group, a pyrrolyl group, an imidazolyl group, an imidazoliogroup, a pyrazolyl group, a thiazolyl group, a pyridyl group, apyridinio group, a pyrazinyl group, a quinolyl group, an isoquinolylgroup, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, amorpholinyl group, a benzothiazolyl group, an isoindolyl group, aquinuclidinyl group, a quinuclidinio group, abenzothiazol-1,1-dioxo-6-yl group or a 1,4-diazabicyclo 2.2.2!octanylgroup which may be substituted with the same or different one to threesubstituents, selected from the group consisting of a hydroxyl group, ahalogen atom, a cyano group, a carboxyl group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a di-loweralkylcarbamoyl group, a carbamoyloxy group, an amino group, a loweralkylamino group, a di-lower alkylamino group, a tri-lower alkylammoniogroup, a formimidoylamino group, an acetimidoylamino group, a loweralkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, asulfo group, a sulfamoyl group, a lower alkylsulfamoyl group, a di-loweralkylsulfamoyl group, a lower alkyl group, a hydroxy lower alkyl groupand a carbamoyl lower alkyl group) which may be substituted with thesame or different one to five substituents selected from the groupconsisting of a lower alkyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a lower alkylamino group, a lower alkoxygroup, an aryloxy group, a lower alkylthio group, a lower alkylsulfonylgroup and a lower alkylsulfamoyl group which may be substituted with thesame or different one to three substituents selected from the groupconsisting of a hydroxyl group, a halogen atom, a cyano group, acarboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a loweralkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxygroup, an amino group, a lower alkylamino group, a di-lower alkylaminogroup, a tri-lower alkylammonio group, a carbamoyl lower alkylaminogroup, an aroylamino group, an amino lower alkyl group, an amino loweralkylcarbonylamino group, a pyridyl group, a pyridylcarbonylamino group,a pyridiniocarbonylamino group, a formimidoylamino group, anacetimidoylamino group, a lower alkoxy group, a lower alkylthio group, asulfo group, an aminosulfonyl group, a lower alkylsulfonyl group and adi-lower alkylsulfonyl group, and a hydroxyl group, a halogen atom, acyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoylgroup, a di-lower alkylcarbamoyl group, an arylcarbamoyl group, apiperazinocarbonyl group, an amino group, a di-lower alkylamino group, atri-lower alkylammonio group, a sulfamino group, a lower alkanoylaminogroup, an aralkylamino group, an aroylamino group, an arylsulfonylaminogroup, an amino lower alkylcarbonylamino group, a sulfamoyl group and adi-lower alkylsulfamoyl group, each of A₁, A₂ and A₃, which may be sameor different, is a single bond or a lower alkylene group which may besubstituted with a substituent selected from the group consisting of alower alkyl group, a lower alkylcarbamoyl group, a lower alkylaminogroup, a lower alkoxy group, a lower alkylthio group, a loweralkylsulfonyl group, a lower alkylsulfonylamino group and a loweralkylsulfamoyl group which may be substituted with the same or differentone to three substituents selected from the group consisting of ahydroxyl group, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino group, alower alkylamino group, a di-lower alkylamino group, a tri-loweralkylammonio group, a formimidoylamino group, an acetimidoylamino group,a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonylgroup, a sulfo group, a sulfamoyl group, a lower alkylsulfamoyl groupand a di-lower alkylsulfamoyl group, and a pyridyl group and a pyridiniogroup (wherein the pyridyl group and the pyridinio group may besubstituted with a substituent selected from the group consisting of alower alkyl group, a carboxy lower alkyl group and a carbamoyl loweralkyl group), and W is a sulfur atom, a group of N--X (wherein X is ahydrogen atom, a lower alkyl group, a formyl group, a lower alkanoylgroup or a sulfamoyl group), an oxygen atom, a group of CH(OH) or asingle bond; or a pharmaceutically acceptable salt or ester thereof, aprocess for its production and its use as an antibacterial agent.

Now, the present invention will be described in detail with reference tothe preferred embodiments. Firstly, the symbols and terms used in thisspecification will be explained.

The compound of the present invention has a basic structure of theformula: ##STR8## which is systematically referred to as a7-oxo-1-azabicyclo 3.2.0!hept-2-en-2-carboxylic acid. For theconvenience sake, in this specification, this basic structure will bereferred to as a 1-carbapen-2-em-3-carboxylic acid by putting thenumbers based on a commonly widely used carbapenem of the formula:##STR9##

The present invention includes optical isomers and stereoisomers basedon the asymmetric carbon atoms at the 1-position, 5-position, 6-positionand 8-position of the carbapenem structure. Among these isomers,preferred is a compound of a (5R,6S,8R) configuration i.e. a compoundhaving a steric configuration of (5R,6S) (5,6-trans) like thienamycinand in which the carbon atom at the 8-position takes a R-configuration,or a compound of a (1R,5S,6S,8R) configuration in a case where a methylgroup is present at the 1-position. ##STR10##

Also with respect to the substituted pyrrolidinylthio group at the2-position of the carbapenem nuclei, the present invention includesisomers based on the asymmetric carbon atoms on the substitutedpyrrolidine nucleus. Among these isomers, preferred are compounds of a(2'S,4'S) configuration and of a (2'R,4'R) configuration.

The mode of the substitution of the pyrrolidine ring in the side chainat the 2-position of the carbapenem structure is not particularlyrestricted, and the pyrrolidine ring may be substituted at anypositions.

Preferred modes of substitution are ##STR11## and the like, and the modeof substitution represented by ##STR12## is particularly preferred.

The lower alkyl group means a linear or branched alkyl group having from1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propylgroup, an isopropyl group, a butyl group, a sec-butyl group, a t-butylgroup, a pentyl group or a hexyl group, preferably a methyl group, anethyl group or a tert-butyl group.

The lower alkanoyl group means an alkanoyl group having from 2 to 7carbon atoms, such as an acetyl group, a propenyl group or a butyrylgroup, preferably an acetyl group.

The halogen atom means a fluorine atom, a chlorine atom, a bromine atomor an iodine atom, preferably a fluorine atom, a chlorine atom or abromine atom.

The lower alkoxy group means a linear or branched alkoxy group havingfrom 1 to 6 carbon atoms with the above lower alkyl group substituted onan oxygen atom, such as a methoxy group, an ethoxy group, a propoxygroup, an isopropoxy group, a butoxy group, a sec-butoxy group, atert-butoxy group, a pentoxy group or a hetoxy group, preferably amethoxy group, an ethoxy group or a t-butoxy group.

The lower alkylthio group means a linear or branched alkylthio grouphaving from 1 to 6 carbon atoms with the above lower alkyl groupsubstituted on a sulfur atom, such as a methylthio group, an ethylthiogroup, a propylthio group, an isopropylthio group, a butylthio group, asec-butylthio group, a t-butylthio group, a pentylthio group or ahexylthio group, preferably a methylthio group, an ethylthio group or at-butylthio group.

The lower alkylcarbamoyl group means an alkylcarbamoyl group having from2 to 7 carbon atoms with the above lower alkyl group substituted on acarbamoyl group, such as a methylcarbamoyl group, an ethylcarbamoylgroup, a propylcarbamoyl group, an isopropylcarbamoyl group, abutylcarbamoyl group, a sec-butylcarbamoyl group, a t-butylcarbamoylgroup, a pentylcarbamoyl group or a hexylcarbamoyl group, preferably amethylcarbamoyl group, an ethylcarbamoyl group or a t-butylcarbamoylgroup.

The di-lower alkylcarbamoyl group means a dialkylcarbamoyl group havingfrom 3 to 13 carbon atoms with the above-mentioned two lower alkylgroups substituted on a carbamoyl group, such as a dimethylcarbamoylgroup, a diethylcarbamoyl group, a dipropylcarbamoyl group, adiisopropylcarbamoyl group, a dibutylcarbamoyl group, adi-sec-butylcarbamoyl group, a di-t-butylcarbamoyl group, adipentylcarbamoyl group, a dihexylcarbamoyl group, anethylmethylcarbamoyl group, a methylpropylcarbamoyl group or at-butylmethylcarbamoyl group, preferably a dimethylcarbamoyl group, adiethylcarbamoyl group or a di-t-butylcarbamoyl group.

The lower alkylamino group means an alkylamino group having from 1 to 6carbon atoms with the above lower alkyl group substituted on an aminogroup, such as a methylamino group, an ethylamino group, a propylaminogroup, an isopropylamino group, a butylamino group, a sec-butylaminogroup, a t-butylamino group, a pentylamino group or a hexylamino group,preferably a methylamino group, an ethylamino group or a t-butylaminogroup.

The di-lower alkylamino group means a dialkylamino group having from 2to 12 carbon atoms with the above-mentioned two lower alkyl groupssubstituted on an amino group, such as a dimethylamino group, adiethylamino group, a dipropylamino group, a diisopropylamino group, adibutylamino group, a di-sec-butylamino group, a di-t-butylamino group,a dipentylamino group, a dihexylamino group, an ethylmethylamino group,a methylpropylamino group, a butylmethylamino group or at-butylmethylamino group, preferably a dimethylamino group, adiethylamino group or a di-t-butylamino group.

The tri-lower alkylammonio group means a trialkylammonio group havingfrom 3 to 18 carbon atoms with the above-mentioned three lower alkylgroups substituted on an amino group, such as a trimethylammonio group,a triethylammonio group, a tripropylammonio group, a triisopropylammoniogroup, a tributylammonio group, a tri-sec-butylammonio group, atri-t-butylammonio group, a tripentylammonio group or a trihexylammoniogroup, preferably a trimethylammonio group, a triethylammonio group or atri-t-butylammonio group.

The lower alkanoylamino group means an alkanoylamino group having from 2to 7 carbon atoms with the above-mentioned lower alkanoyl groupsubstituted on an amino group, such as an acetylamino group, apropionylamino group or a butyrylamino group, preferably an acetylaminogroup or a propionylamino group.

The lower alkoxycarbonyl group means an alkoxycarbonyl group having from2 to 7 carbon atoms with the above lower alkoxy groups substituted on acarbonyl group, such as a methoxycarbonyl group, an ethoxycarbonylgroup, a propoxycarbonyl group, an isopropoxycarbonyl group, abutoxycarbonyl group, a sec-butoxycarbonyl group, a t-butoxycarbonylgroup, a pentoxycarbonyl group or a hetoxycarbonyl group, preferably amethoxycarbonyl group, an ethoxycarbonyl group or a t-butoxycarbonylgroup.

The carbamoyl lower alkylamino group means a carbamoylalkylamino grouphaving from 2 to 7 carbon atoms with a carbamoyl group substituted onthe above lower alkylamino group, such as a carbamoylmethylamino group,a 1-carbamoylethylamino group, a 2-carbamoylethylamino group, a1-carbamoylpropylamino group, a 2-carbamoylpropylamino group, a3-carbamoylpropylamino group, a 2-carbamoyl-1-methylethylamino group, a1-carbamoylbutylamino group, a 2-carbamoylbutylamino group, a3-carbamoylbutylamino group, a 4-carbamoylbutylamino group, a2-carbamoyl-1,1-dimethylamino group, a 1-carbamoylpentylamino group, a2-carbamoylpentylamino group, a 3-carbamoylpentylamino group, a4-carbamoylpentylamino group, a 5-carbamoylpentylamino group, a1-carbamoylhexylamino group, a 2-carbamoylhexylamino group, a3-carbamoylhexylamino group, a 4-carbamoylhexylamino group, a5-carbamoylhexylamino group or a 6-carbamoylhexylamino group, preferablya carbamoylmethylamino group, a 2-carbamoylethylamino group or a2-carbamoyl-1,1-dimethylamino group.

The amino lower alkyl group means an aminoalkyl group having from 1 to 6carbon atoms with an amino group substituted on the above lower alkylgroup, such as an aminomethyl group, a 1-aminoethyl group, a2-aminoethyl group, a 1-aminopropyl group, a 2-aminopropyl group, a3-aminopropyl group, a 2-amino-1-methylethyl group, a 1-aminobutylgroup, a 2-aminobutyl group, a 3-aminobutyl group, a 4-aminobutyl group,a 2-amino-1,1-dimethyl group, a 1-aminopentyl group, a 2-aminopentylgroup, a 3-aminopentyl group, a 4-aminopentyl group, a 5-aminopentylgroup, a 1-aminohexyl group, a 2-aminohexyl group, 3-aminohexyl group, a4-aminohexyl group, a 5-aminohexyl group or a 6-aminohexyl group,preferably an aminomethyl group, a 2-aminoethyl group or a2-amino-1,1-dimethyl group.

The carboxy lower alkyl group means a carboxyalkyl group having from 1to 6 carbon atoms with a carboxyl group substituted on the above loweralkyl group, such as a carboxymethyl group, a 1-carboxyethyl group, a2-carboxyethyl group, a 1-carboxypropyl group, a 2-carboxypropyl group,a 3-carboxypropyl group, a 2-carboxy-1-methylethyl group, a1-carboxybutyl group a 2-carboxybutyl group, a 3-carboxybutyl group, a4-carboxybutyl group, a 2-carboxy-1,1-dimethyl group, a 1-carboxypentylgroup, a 2-carboxypentyl group, a 3-carboxypentyl group, a4-carboxypentyl group, a 5-carboxypentyl group, a 1-carboxyhexyl group,a 2-carboxyhexyl group, a 3-carboxyhexyl group, a 4-carboxyhexyl group,a 5-carboxyhexyl group or a 6-carboxyhexyl group, preferably acarboxymethyl group, a 2-carboxyethyl group or a 2-carboxy-1,1-dimethylgroup.

The carbamoyl lower alkyl group means a carbamoylalkyl group having from1 to 6 carbon atoms with a carbamoyl group substituted on the abovelower alkyl group, such as a carbamoylmethyl group, a 1-carbamoylethylgroup, a 2-carbamoylethyl group, a 1-carbamoyl propyl group, a2-carbamoylpropyl group, a 3-carbamoylpropyl group, a2-carbamoyl-1-methylethyl group, a 1-carbamoylbutyl group, a2-carbamoylbutyl group, a 3-carbamoylbutyl group, a 4-carbamoylbutylgroup, a 2-carbamoyl-1,1-dimethyl group, a 1-carbamoylpentyl group, a2-carbamoylpentyl group, a 3-carbamoylpentyl group, a 4-carbamoylpentylgroup, a 5-carbamoylpentyl group, a 1-carbamoylhexyl group, a2-carbamoylhexyl group, a 3-carbamoylhexyl group, a 4-carbamoylhexylgroup, a 5-carbamoylhexyl group or a 6-carbamoylhexyl group, preferablya carbamoylmethyl group, a 2-carbamoylethyl group or a2-carbamoyl-1,1-dimethyl group.

The hydroxy lower alkyl group means a hydroxyalkyl group having from 1to 6 carbon atoms with a hydroxy group substituted on the above loweralkyl group, such as a hydroxymethyl group, a 1-hydroxyethyl group, a2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropyl group,a 3-hydroxypropyl group, a 2-hydroxy-1-methylethyl group, a1-hydroxybutyl group, a 2-hydroxybutyl group, a 3-hydroxybutyl group, a4-hydroxybutyl group, a 2-hydroxy-1,1-dimethyl group, a 1-hydroxypentylgroup, a 2-hydroxypentyl group, a 3-hydroxypentyl group, a4-hydroxypentyl group, a 5-hydroxypentyl group, a 1-hydroxyhexyl group,a 2-hydroxyhexyl group, a 3-hydroxyhexyl group, a 4-hydroxyhexyl group,a 5-hydroxyhexyl group or a 6-hydroxyhexyl group, preferably ahydroxymethyl group, a 2-hydroxyethyl group or a 2-hydroxy-1,1-dimethylgroup.

The amino lower alkylcarbonylamino group means anaminoalkylcarbonylamino group having from 2 to 7 carbon atoms with theabove amino lower alkyl group substituted on a carbonylamino group, suchas an aminomethylcarbonylamino group, a 1-aminoethylcarbonylamino group,a 2-aminoethylcarbonylamino group, a 1-aminopropylcarbonylamino group, a2-aminopropylcarbonylamino group, a 3-aminopropylcarbonylamino group, a2-amino-1-methylethylcarbonylamino group, a 1-aminobutylcarbonylaminogroup, a 2-aminobutylcarbonylamino group, a 3-aminobutylcarbonylaminogroup, a 4-aminobutylcarbonylamino group, a2-amino-1,1-dimethylcarbonylamino group, a 1-aminopentylcarbonylaminogroup, a 2-aminopentylcarbonylamino group, a 3-aminopentylcarbonylaminogroup, a 4-aminopentylcarbonylamino group, a 5-aminopentylcarbonylaminogroup, a 1-aminohexylcarbonylamino group, a 2-aminohexylcarbonylaminogroup, a 3-aminohexylcarbonylamino group, a 4-aminohexylcarbonylaminogroup, a 5-aminohexylcarbonylamino group or a 6-aminohexylcarbonylaminogroup, preferably an aminomethylcarbonylamino group, a2-aminoethylcarbonylamino group or a 2-amino-1,1-dimethylcarbonylaminogroup.

The lower alkylsulfonyl group means a linear or branched alkylsulfonylgroup having from 1 to 6 carbon atoms with the above lower alkyl groupsubstituted on a sulfonyl group, such as a methylsulfonyl group, anethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group,a butylsulfonyl group, a sec-butylsulfonyl group, a t-butylsulfonylgroup, a pentylsulfonyl group or a hexylsulfonyl group, preferably amethylsulfonyl group, an ethylsulfonyl group or a t-butylsulfonyl group.

The di-lower alkylsulfonyl group means a dialkylsulfonyl group havingfrom 2 to 12 carbon atoms with the above-mentioned two lower alkylgroups substituted on a sulfonyl group, such as a dimethylsulfonylgroup, a diethylsulfonyl group, a dipropylsulfonyl group, adiisopropylsulfonyl group, a dibutylsulfonyl group, adi-sec-butylsulfonyl group, a di-t-butylsulfonyl group, adipentylsulfonyl group, a dihexylsulfonyl group, an ethylmethylsulfonylgroup, a methylpropylsulfonyl group or a t-butylmethylsulfonyl group,preferably a dimethylsulfonyl group, a diethylsulfonyl group or adi-t-butylsulfonyl group.

The lower alkylsulfamoyl group means a linear or branched alkylsulfamoylgroup having from 1 to 6 carbon atoms with the above lower alkyl groupsubstituted on a sulfamoyl group, such as a methylsulfamoyl group, anethylsulfamoyl group, a propylsulfamoyl group, an isoproylsulfamoylgroup, a butylsulfamoyl group, a sec-butylsulfamoyl group, at-butylsulfamoyl group, a pentylsulfamoyl group or a hexylsulfamoylgroup, preferably a methylsulfamoyl group, an ethylsulfamoyl group or at-butylsulfamoyl group.

The di-lower alkylsulfamoyl group means a dialkylsuifamoyl group havingfrom 2 to 12 carbon atoms with the above two lower alkyl groupssubstituted on a sulfamoyl group, such as a dimethylsulfamoyl group, adiethylsulfamoyl group, a dipropylsulfamoyl group, adiisopropylsulfamoyl group, a dibutylsulfamoyl group, adi-sec-butylsulfamoyl group, a di-t-butylsulfamoyl group, adipentylsulfamoyl group, a di-hexylsulfamoyl group, anethylmethylsulfamoyl group, a methylpropylsulfamoyl group or at-butylmethylsulfamoyl group, preferably a dimethylsulfamoyl group, adiethylsulfamoyl group or a di-t-butylsulfamoyl group.

The lower alkylsulfonylamino group means a linear or branchedalkylsulfonylamino group having from 1 to 6 carbon atoms with the abovelower alkyl sulfonyl group substituted on an amino group, such as amethylsulfonylamino group, an ethylsulfonylamino group, apropylsulfonylamino group, an isopropylsulfonylamino group, abutylsulfonylamino group, a sec-butylsulfonylamino group, at-butylsulfonylamino group, a pentylsulfonylamino group or ahexylsulfonylamino group, preferably a methylsulfonylamino group, anethylsulfonylamino group or a t-butylsulfonylamino group.

The aryl group means an aryl group having from 6 to 12 carbon atoms,such as a phenyl group or an naphthyl group, preferably a phenyl group.

The aryloxy group means an aryloxy group having from 6 to 12 carbonatoms with the above aryl group substituted on an oxygen atom, such as aphenoxy group or a naphthoxy group, preferably a phenoxy group.

The arylthio group means an arylthio group having from 6 to 12 carbonatoms with the above aryl group substituted on a sulfur atom, such as aphenylthio group or a naphthylthio group, preferably a phenylthio group.

The arylcarbamoyl group means an arylcarbamoyl group having from 7 to 13carbon atoms with the above aryl group substituted on a carbamoyl group,such as a phenylcarbamoyl group or a naphthylcarbamoyl group, preferablya phenylcarbamoyl group,

The arylsulfonyl group means an arylsulfonyl group having from 6 to 12carbon atoms with the above aryl group substituted on a sulfonyl group,such as a phenylsulfonyl group or a naphthylsulfonyl group, preferably aphenylsulfonyl group.

The aryloxycarbonyl group means an aryloxycarbonyl group having from 6to 12 carbon atoms with the aryloxy group substituted on a carbonylgroup, such as a phenoxycarbonyl group or a naphthoxycarbonyl group,preferably a phenoxycarbonyl group.

The arylsulfonylamino group means an arylsulfonylamino group having from6 to 12 carbon atoms with the above arylsulfonyl group substituted on anamino group, such as a phenylsulfonylamino group or anaphthylsulfonylamino group, preferably a phenylsulfonylamino group.

The aralkyl group means an aralkyl group having from 7 to 14 carbonatoms, such as a benzyl group, a phenethyl group, a phenylpropyl group,a phenylbutyl group, a naphthylmethyl group, a naphthylethyl group, anaphthylpropyl group or a naphthylbutyl group, preferably a benzylgroup, a phenethyl group, a naphthylmethyl group or a naphthylethylgroup.

The aralkylamino group means an aralkylamino group having from 7 to 14carbon atoms with the above aralkyl group substituted on an amino group,such as a benzylamino group, a phenethylamino group, a phenylpropylaminogroup, a phenylbutylamino group, a naphthylmethylamino group, anaphthylethylamino group, a naphthylpropylamino group or anaphthylbutylamino group, preferably a benzylamino group, aphenethylamino group, a naphthylmethylamino group or anaphthylethylamino group.

The aroyl group means an aroyl group having from 7 to 11 carbon atoms,such as a benzoyl group, toluoyl group or a naphthylcarbonyl group.

The aroylamino group means an aroylamino group having from 7 to 14carbon atoms with the above aroyl group substituted on an amino group,such as a benzoylamino group, a toluoylamino group or anaphthylcarbonylamino group, preferably a benzoylamino group.

The lower alkylene group means a linear or branched alkylene grouphaving from 1 to 6 carbon atoms, such as a methylene group, an ethylenegroup, a propylene group, a butylene group, a methylmethylene group or adimethylmethylene group, preferably a methylene group, an ethylene groupor a propylene group.

The carboxyl-protecting group may, for example, be a lower alkyl groupsuch as a methyl group, an ethyl group, a propyl group, an isopropylgroup or a t-butyl group; a halogenated lower alkyl group such as a2,2,2-trichloroethyl group or a 2,2,2-trifluoroethyl group; a loweralkanoyloxyalkyl group such as an acetoxymethyl group, apropionyloxymethyl group, a pivaloyloxymethyl group, a 1-acetoxyethylgroup or a 1-propionyloxyethyl group; a lower alkoxycarbonyloxyalkylgroup such as a 1-(methoxycarbonyloxy)ethyl group, a1-(ethoxycarbonyloxy)ethyl group or a 1-(isopropoxycarbonyloxy)ethylgroup; a lower alkenyl group such as a 2-propenyl group, a2-chloro-2-propenyl group, a 3-methoxycarbonyl-2-propenyl group, a2-methyl-2-propenyl group, a 2-butenyl group or a cinnamyl group; anaralkyl group such as a benzyl group, a p-methoxybenzyl group, a3,4-dimethoxybenzyl group, an o-nitrobenzyl group, a p-nitrobenzylgroup, a benzhydryl group or a bis(p-methoxyphenyl)methyl group; a(5-substituted-2-oxo-1,3-dioxol-4-yl)methyl group such as a(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group; a lower alkylsilyl groupsuch as a trimethylsilyl group or a t-butyldimethylsilyl group; anindanyl group, a phthalidyl group or a methoxymethyl group. Particularlypreferred are a 2-propenyl group, a p-nitrobenzyl group, ap-methoxybenzyl group, a benzhydryl group and a t-butyldimethylsilylgroup.

The hydroxyl-protecting group may, for example, be a lower alkylsilylgroup such as a trimethylsilyl group or a t-butyldimethylsilyl group; alower alkoxymethyl group such as a methoxymethyl group or a2-methoxyethoxymethyl group; a tetrahydropyranyl group; an aralkyl groupsuch as a benzyl group, a p-methoxybenzyl group, a 2,4-dimethoxybenzylgroup, an o-nitrobenzyl group, a p-nitrobenzyl group or a trityl group;an acyl group such as a formyl group or an acetyl group; a loweralkoxycarbonyl group such as a t-butoxycarbonyl group, an2-iodoethoxycarbonyl group or a 2,2,2-trichloroethoxycarbonyl group; analkenyloxycarbonyl group such as a 2-propenyloxycarbonyl group, a2-chloro-2-propenyloxycarbonyl group, a3-methoxycarbonyl-2-propenyloxycarbonyl group, a2-methyl-2-propenyloxycarbonyl group, a 2-butenyloxycarbonyl group or acinnamyloxycarbonyl group; or an aralkyloxycarbonyl group such as abenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, ano-nitrobenzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group.Particularly preferred are a 2-propenyloxycarbonyl group, ap-nitrobenzyloxycarbonyl group and a t-butyldimethylsilyl group.

The amino-protecting group may, for example, be an aralkylidene groupsuch as a benzylidene group, a p-chlorobenzylidene group, ap-nitrobenzylidene group, a salicylidene group, an α-naphthylidene groupor a β-naphthylidene group; an aralkyl group such as a benzyl group, ap-methoxybenzyl group, a 3,4-dimethoxybenzyl group, an o-nitrobenzylgroup, a p-nitrobenzyl group, a benzhydryl group, abis(p-methoxyphenyl)methyl group or a trityl group; a lower alkanoylgroup such as a formyl group, an acetyl group, a propionyl group, abutyryl group, an oxalyl group, a succinyl group or a pivaloyl group; ahalogenated lower alkanoyl group such as a chloroacetyl group, adichloroacetyl group, a trichloroacetyl group or a trifluoroacetylgroup; an arylalkanoyl group such as a phenylacetyl group or aphenoxyacetyl group; a lower alkoxycarbonyl group such as amethoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl groupor a t-butoxycarbonyl group; a halogenated lower alkoxycarbonyl groupsuch as a 2-iodoethoxycarbonyl group or a 2,2,2-trichloroethoxycarbonylgroup; an alkenyloxycarbonyl group such as a 2-propenyloxycarbonylgroup, a 2-chloro-2-propenyloxycarbonyl group, a3-methoxycarbonyl-2-propenyloxycarbonyl group, a2-methyl-2-propenyloxycarbonyl group, a 2-butenyloxycarbonyl group or acinnamyloxycarbonyl group; an aralkyloxycarbonyl group such as abenzyloxycarbonyl group, an o-nitrobenzyloxycarbonyl group, ap-nitrobenzyloxycarbonyl group or a phenethyloxycarbonyl group; or alower alkylsilyl group such as a trimethylsilyl group or at-butyldimethylsilyl group. Particularly preferred are a2-propenyloxycarbonyl group, a t-butoxycarbonyl group and ap-nitrobenzyloxycarbonyl group.

R¹ is a hydrogen atom or a lower alkyl group.

R² is a hydrogen atom or a negative charge.

R³ is a hydrogen atom or a lower alkyl group.

Ar is a phenyl group, a naphthyl group or a group of: ##STR13## (whereineach of A₄ and A₅, which may be the same or different, is a single bond,a methylene group, an ethylene group, an oxygen atom, an imino group, asulfur atom, a sulfonyl group, --CONH-- or --NHSO₂ --, and Het is apyrrolinyl group, a pyrrolyl group, an imidazolyl group, an imidazoliogroup, a pyrazolyl group, a thiazolyl group, a pyridyl group, apyridinio group, a pyrazinyl group, a quinolyl group, an isoquinolylgroup, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, amorpholinyl group, a benzothiazolyl group, an isoindolyl group, aquinuclidinyl group, a quinuclidinio group, abenzothiazol-1,1-dioxo-6-yl group or a 1,4-diazabicyclo 2.2.2!octanylgroup which may be substituted with the same or different one to threesubstituents, selected from the group consisting of a hydroxyl group, ahalogen atom, a cyano group, a carboxyl group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a di-loweralkylcarbamoyl group, a carbamoyloxy group, an amino group, a loweralkylamino group, a di-lower alkylamino group, a tri-lower alkylammoniogroup, a formimidoylamino group, an acetimidoylamino group, a loweralkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, asulfo group, a sulfamoyl group, a lower alkylsulfamoyl group, a di-loweralkylsulfamoyl group, a lower alkyl group, a hydroxy lower alkyl groupand a carbamoyl lower alkyl group).

The above-mentioned phenyl group, the above-mentioned naphthyl group orthe aryl group in the group of: ##STR14## (wherein A⁴, A⁵ and Het are asdefined above) may be substituted with the same or different one to fivesubstituents selected from the group consisting of a lower alkyl group,a lower alkylcarbamoyl group, a lower alkylsulfonylamino group, a loweralkylamino group, a lower alkoxy group, an aryloxy group, a loweralkylthio group, a lower alkylsulfonyl group, a lower alkylsulfamoylgroup, a hydroxyl group, a halogen atom, a cyano group, a carboxylgroup, a lower alkoxycarbonyl group, a carbamoyl group, a di-loweralkylcarbamoyl group, an arylcarbamoyl group, a piperazinocarbonylgroup, an amino group, a di-lower alkylamino group, a tri-loweralkylammonio group, a sulfamino group, a lower alkanoylamino group, anaralkylamino group, an aroylamino group, an arylsulfonylamino group, anamino lower alkylcarbonylamino group, a sulfamoyl group and a di-loweralkylsulfamoyl group. Among this group of substituents, the lower alkylgroup, the lower alkylcarbamoyl group, the lower alkylsulfonylaminogroup, the lower alkylamino group, the lower alkoxy group, the aryloxygroup, the lower alkylthio group, the lower alkylsulfonyl group and thelower alkylsulfamoyl group may be substituted with the same or differentone to three substituents, selected from the group consisting of ahydroxyl group, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino group, alower alkylamino group, a di-lower alkylamino group, a tri-loweralkylammonio group, a carbamoyl lower alkylamino group, an aroylaminogroup, an amino lower alkyl group, an amino lower alkylcarbonylaminogroup, a pyridyl group, a pyridylcarbonylamino group, apyridiniocarbonylamino group, a formimidoylamino group, anacetimidoylamino group, a lower alkoxy group, a lower alkylthio group, asulfo group, an aminosulfonyl group, a lower alkylsulfonyl group and adi-lower alkylsulfonyl group.

Among the substituents for the aryl group, preferred are a lower alkylgroup, a lower alkylcarbamoyl group, a lower alkylsulfonylamino group, alower alkylamino group, a lower alkoxy group, a lower alkylthio group, alower alkylsulfonyl group, a lower alkylsulfamoyl group, a hydroxylgroup, a halogen atom, a carboxyl group, a carbamoyl group, an aminogroup and a sulfamoyl group. Particularly preferred are an amino groupand a lower alkyl group.

Among the substituents for the substituents for the aryl group,preferred are a hydroxyl group, a carboxyl group, a carbamoyl group, anamino group and a lower alkylamino group. Particularly preferred are anamino group and a lower alkylamino group.

As Ar, preferred is Ar_(a), which is a phenyl group, a naphthyl group ora group of: ##STR15## (wherein each of A_(4a) and A_(5a), which may bethe same or different, is a single bond, a methylene group or anethylene group, and Het^(a) is an imidazolio group, a pyridinio group, amorpholinyl group, a quinuclidinio group or a 1,4-diazabicyclo2.2.2!octanyl group which may be substituted with the same or differentone to three substituents selected from the group consisting of a loweralkyl group, a hydroxy lower alkyl group and a carbamoyl lower alkylgroup) which may be substituted with the same or different one to fivesubstituents selected from the group consisting of a lower alkyl group,a lower alkylcarbamoyl group, a lower alkylsulfonylamino group, a loweralkylamino group, a lower alkoxy group, a lower alkylthio group, a loweralkylsulfonyl group and a lower alkylsulfamoyl group which may besubstituted with the same or different one to three substituentsselected from the group consisting of a hydroxyl group, a carboxylgroup, a carbamoyl group, an amino group and a lower alkylamino group,and a hydroxyl group, a halogen atom, a carboxyl group, a carbamoylgroup, an amino group and a sulfamoyl group. Particularly preferred isAr_(b), which is a phenyl group, a naphthyl group or a group of:##STR16## (wherein each of A_(4b) and A_(5b), which may be the same ordifferent, is a single bond, a methylene group or an ethylene group, andHet^(b) is an imidazolio group or a 1,4-diazabicyclo 2.2.2!octanyl groupwhich may be substituted with the same or different one to threesubstituents selected from the group consisting of a hydroxy lower alkylgroup and a carbamoyl lower alkyl group) which may be substituted withthe same or different one to five substituents selected from the groupconsisting of a lower alkyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a lower alkylthio group, a lower alkylsulfonylgroup and a lower alkylsulfamoyl group which may be substituted with thesame or different one to three substituents selected from the groupconsisting of an amino group and a lower alkylamino group, and a halogenatom, a carbamoyl group and a sulfamoyl group.

Each of A₄ and A₅, which may be the same or different, is a single bond,a methylene group, an ethylene group, an oxygen atom, an imino group, asulfur atom, a sulfonyl group, --CONH-- or --NHSO₂ --.

As A₄ and A₅, preferred are A_(4a) and A_(5a), and A_(4b) and A_(5h),which may be the same or different, and each of which is a single bond,a methylene group or an ethylene group. When A₄ or A₅ is --CONH-- or--NHSO₂ --, A₄ and A₅ may be linked to the benzene ring or theheterocyclic group in the order of --CONH-- or --NHCO-- via the carbonatom or the nitrogen atom, or in the order of --NHSO₂ -- or --SO₂ NH--via the nitrogen atom or the sulfur atom.

Het is a heterocyclic group such as a pyrrolinyl group, a pyrrolylgroup, an imidazoyl group, an imidazolio group, a pyrazolyl group, athiazolyl group, a pyridyl group, a pyridinio group, a pyrazinyl group,a quinolyl group, an isoquinolyl group, a pyrrolidinyl group, apiperidyl group, a piperazinyl group, a morpholinyl group, abenzothiazolyl group, an isoindolyl group, a quinuclidinyl group, aquinuclidinio group, a benzothiazol-1,1-dioxo-6-yl group or a1,4-diazabicyclo 2.2.2!octanyl group.

The heterocyclic group may be substituted with the same or different oneto three substituents selected from the group consisting of a hydroxylgroup, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino group, alower alkylamino group, a di-lower alkylamino group, a tri-loweralkylammonio group, a formimidoylamino group, an acetimidoylamino group,a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonylgroup, a sulfo group, a sulfamoyl group, a lower alkylsulfamoyl group, adi-lower alkylsulfamoyl group, a lower alkyl group, a hydroxy loweralkyl group and a carbamoyl lower alkyl group.

As the heterocyclic group, preferred are an imidazolio group, apyridinio group, a morpholinyl group, a quinuclidinio group and a1,4-diazabicyclo 2.2.2!octanyl group. Particularly preferred are animidazolio group and a 1,4-diazabicyclo 2.2.2!octanyl group.

As the substituents for the heterocyclic group, preferred are a loweralkyl group, a hydroxy lower alkyl group and a carbamoyl lower alkylgroup, and particularly preferred are a hydroxy lower alkyl group and acarbamoyl lower alkyl group. The heterocyclic group may be substitutedwith the same or different one to three substituents selected from thesesubstituents.

Accordingly, as Het, preferred is Het^(a), which is an imidazolio group,a pyridinio group, a morpholinyl group, a quinuclidinio group or a1,4-diazabicyclo 2.2.2!octanyl group which may be substituted with thesame or different one to three substituents selected from the groupconsisting of a lower alkyl group, a hydroxy lower alkyl group and acarbamoyl lower alkyl group. Particularly preferred is Het^(b), which isan imidazolio group or a 1,4-diazabicyclo 2.2.2!octanyl group which maybe substituted with the same or different one to three substituentsselected from the group consisting of a hydroxy lower alkyl group and acarbamoyl lower alkyl group.

Each of A₁, A₂ and A₃, which may be the same or different, is a singlebond or a lower alkylene group.

The lower alkylene group may be substituted with a substituent selectedfrom the group consisting of a lower alkyl group, a lower alkylcarbamoylgroup, a lower alkylamino group, a lower alkoxy group, a lower alkylthiogroup, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, alower alkylsulfamoyl group, a pyridyl group and a pyridinio group. Amongthese substituents, the lower alkyl group, the lower alkylcarbamoylgroup, the lower alkylamino group, the lower alkoxy group, the loweralkylthio group, the lower alkylsulfonyl group, the loweralkylsulfonylamino group and the lower alkylsulfamoyl group (hereinafterreferred to as substituent group A) may be substituted with the same ordifferent one to three substituents selected from the group consistingof a hydroxyl group, a halogen atom, a cyano group, a carboxyl group, alower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoylgroup, a di-lower alkylcarbamoyl group, a carbamoyloxy group, an aminogroup, a lower alkylamino group, a di-lower alkylamino group, atri-lower alkylammonio group, a formimidoylamino group, anacetimidoylamino group, a lower alkoxy group, a lower alkylthio group, alower alkylsulfonyl group, a sulfo group, a sulfamoyl group, a loweralkylsulfamoyl group and a di-lower alkylsulfamoyl group (hereinafterreferred to simply as substituent group B).

Among substituent group A, preferred are a lower alkyl group, a loweralkylcarbamoyl group, a lower alkylamino group, a lower alkoxy group, alower alkylthio group, a lower alkylsulfonyl group, a loweralkylsulfonylamino group and a lower alkylsulfamoyl group. Particularlypreferred is a lower alkyl group.

Among substituent group B, preferred are a hydroxyl group, a carbamoylgroup, an amino group, a lower alkylamino group and a lower alkylthiogroup. Particularly preferred are a carbamoyl group, an amino group anda lower alkylamino group.

The pyridyl group and the pyridinio group may be substituted with asubstituent selected from the group consisting of a lower alkyl group, acarboxy lower alkyl group and a carbamoyl lower alkyl group.

Therefore, as A₁, A₂ and A₃, preferred are A_(1a), A_(2a) and A_(3a),which may be the same or different, and each of which is a single bondor a lower alkylene group which may be substituted with a substituentselected from the group consisting of a lower alkyl group, a loweralkylcarbamoyl group, a lower alkylamino group, a lower alkoxy group, alower alkylthio group, a lower alkylsulfonyl group, a loweralkylsulfonylamino group and a lower alkylsulfamoyl group which may besubstituted with the same or different one to three substituents,selected from the group consisting of a hydroxyl group, a carbamoylgroup, an amino group, a lower alkylamino group and a lower alkylthiogroup, and a pyridyl group and a pyridinio group (wherein the pyridylgroup and the pyridinio group may be substituted with a substituentselected from the group consisting of a lower alkyl group, a carboxylower alkyl group and a carbamoyl lower alkyl group). Particularlypreferred are A_(1b), A_(2b) and A_(3b), which may be the same ordifferent, and each of which is a single bond or a lower alkylene groupwhich may be substituted with a substituent selected from the groupconsisting of a lower alkyl group which may be substituted with the sameor different one to three substituents selected from the groupconsisting of a carbamoyl group, an amino group and a lower alkylaminogroup, and a pyridyl group and a pyridinio group (wherein the pyridylgroup and the pyridinio group may be substituted with a substituentselected from the group consisting of a lower alkyl group, a carboxylower alkyl group and a carbamoyl lower alkyl group).

W is a sulfur atom, a group of N--X (wherein X is a hydrogen atom, alower alkyl group, a formyl group, a lower alkanoyl group or a sulfamoylgroup), an oxygen atom, a group of CH(OH) or a single bond. Particularlypreferred is a sulfur atom. However, compounds of the present inventionwherein W is a group of N--X (wherein X is a hydrogen atom, a loweralkyl group, a formyl group, a lower alkanoyl group or a sulfamoylgroup), an oxygen atom, a group of CH(OH) or a single bond, also exhibitgood antibacterial activities.

Now, the compounds of the formula I! will be described in detail.

Among the compounds of the formula I!, preferred are compoundsrepresented by the formula: ##STR17## wherein R^(1a) is a lower alkylgroup, R^(2a) is a hydrogen atom or a negative charge, R^(3a) is ahydrogen atom, Ar_(a) is a phenyl group, a naphthyl group or a group of:##STR18## (wherein each of A_(4a) and A_(5a), which may be the same ordifferent, is a single bond, a methylene group or an ethylene group, andHet^(a) is an imidazolio group, a pyridinio group, a morpholinyl group,a quinuclidinio group or a 1,4-diazabicyclo 2.2.2!octanyl group whichmay be substituted with the same or different one to three substituentsselected from the group consisting of a lower alkyl group, a hydroxylower alkyl group and a carbamoyl lower alkyl group) which may besubstituted with the same or different one to five substituents selectedfrom the group consisting of a lower alkyl group, a lower alkylcarbamoylgroup, a lower alkylsulfonylamino group, a lower alkylamino group, alower alkoxy group, a lower alkylthio group, a lower alkylsulfonyl groupand a lower alkylsulfamoyl group which may be substituted with the sameor different one to three substituents selected from the groupconsisting of a hydroxyl group, a carboxyl group, a carbamoyl group, anamino group and a lower alkylamino group, and a hydroxyl group, ahalogen atom, a carboxyl group, a carbamoyl group, an amino group and asulfamoyl group, each of A_(1a), A_(2a) and A_(3a), which may be thesame or different, is a single bond or a lower alkylene group which maybe substituted with a substituent selected from the group consisting ofa lower alkyl group, a lower alkylcarbamoyl group, a lower alkylaminogroup, a lower alkoxy group, a lower alkylthio group, a loweralkylsulfonyl group, a lower alkylsulfonylamino group and a loweralkylsulfamoyl group which may be substituted with the same or differentone to three substituents selected from the group consisting of ahydroxyl group, a carbamoyl group, an amino group, a lower alkylaminogroup and a lower alkylthio group, and a pyridyl group and a pyridiniogroup (wherein the pyridyl group and the pyridinio group may besubstituted with a substituent selected from the group consisting of alower alkyl group, a carboxy lower alkyl group and a carbamoyl loweralkyl group), and W_(a) is a sulfur atom, a group of N--X_(a) (whereinX_(a) is a hydrogen atom, a lower alkyl group, a formyl group, a loweralkanoyl group or a sulfamoyl group), an oxygen atom, a group of CH(OH)or a single bond. Particularly preferred are those wherein W_(a) is asulfur atom. However, compounds wherein W_(a) is a group of N--X_(a)(wherein X_(a) is a hydrogen atom, a lower alkyl group, a formyl group,a lower alkanoyl group or a sulfamoyl group), an oxygen atom, a group ofCH(OH) or a single bond, compounds wherein W_(a) is a group of N--X_(a)(wherein X_(a) is a hydrogen atom, a lower alkyl group, a formyl group,a lower alkanoyl group or a sulfamoyl group), compounds wherein W_(a) isan oxygen atom, compounds wherein W_(a) is a group of CH(OH) andcompounds wherein W_(a) is a single bond also have good antibacterialactivities.

Among the compounds of the formula I-a!, more preferred are compoundsrepresented by the formula: ##STR19## wherein R^(1b) is a lower alkylgroup, R^(2b) is a hydrogen atom or a negative charge, R^(3b) is ahydrogen atom, Ar_(b) is a phenyl group, a naphthyl group or a group of:##STR20## (wherein each of A_(4b) and A_(5b), which may be the same ordifferent, is a single bond, a methylene group or an ethylene group, andHet^(b) is an imidazolio group or a 1,4-diazabicyclo 2.2.2!octanyl groupwhich may be substituted with the same or different one to threesubstituents selected from the group consisting of a hydroxy lower alkylgroup and a carbamoyl lower alkyl group) which may be substituted withthe same or different one to five substituents selected from the groupconsisting of a lower alkyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a lower alkylthio group, a lower alkylsulfonylgroup and a lower alkylsulfamoyl group which may be substituted with thesame or different one to three substituents selected from the groupconsisting of an amino group and a lower alkylamino group, and a halogenatom, a carbamoyl group and a sulfamoyl group, each of A_(1b), A_(2b)and A_(3b), which may be the same or different, is a single bond or alower alkylene group which may be substituted with a substituentselected from the group consisting of a lower alkyl group which may besubstituted with the same or different one to three substituentsselected from the group consisting of a carbamoyl group, an amino groupand a lower alkylamino group, and a pyridyl group and a pyridinio group(wherein the pyridyl group and the pyridinio group may be substitutedwith a substituent selected from the group consisting of a lower alkylgroup, a carboxy lower alkyl group and a carbamoyl lower alkyl group),and W_(b) is a sulfur atom, a group of N--X_(b) (wherein X_(b) is ahydrogen atom, a lower alkyl group, a formyl group, a lower alkanoylgroup or a sulfamoyl group), an oxygen atom, a group of CH(OH) or asingle bond. Thereamong, particularly preferred are those wherein W_(b)is a sulfur atom. However, compounds wherein W_(b) is a group ofN--X_(b) (wherein X_(b) is a hydrogen atom, a lower alkyl group, aformyl group, a lower alkanoyl group or a sulfamoyl group), an oxygenatom, a group of CH(OH) or a single bond, compounds wherein W_(b) is agroup of N--X_(b) (wherein W_(b) is a hydrogen atom, a lower alkylgroup, a formyl group, a lower alkanoyl group or a sulfamoyl group),compounds wherein W_(b) is an oxygen atom, compounds wherein W_(b) is agroup of CH(OH) or compounds wherein W_(b) is a single bond, also havegood antibacterial activities.

Specifically, among the compounds of the formula I!, preferred are, forexample, (1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylthio)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-(3-aminomethyl-4-chlorophenyl)thiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethyl-2-sulfamoylphenyl)thiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylcarbamoyl)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylcarbamoyl)-2-sulfamoylphenyl!thiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethyloxy)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-(3-aminopropionylamino)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylsulfonylamino)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-aminomethylphenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylsulfamoyl)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2-(3S,5S)-5-(8-aminomethyl-2-naphthylmethylthiomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2-(3S,5S)-5-(3-aminomethyl-5-glycylamino-2-naphthylmethylthiomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-(3-aminoethylsulfonylaminoethyl)-2-naphthylmethylthiomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2-(3S,5S)-5-(3-aminomethyl-5-glycylaminomethyl-2-naphthylmethylthiomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5- 6-(4-carbamoylmethyl-1,4-diazabicyclo2.2.2!octanedium-1-ylmethyl)-2-naphthylmethylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5- 3-(4-carbamoylmethyl-1,4-diazabicyclo2.2.2!octanedium-1-ylmethyl)-2naphthylmethylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethylphenylaminomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethyl-1-naphthylaminomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethylphenoxymethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethylphenylethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethylbenzyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethyl-1-naphthylmethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethylphenyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethyl-5-phenylphenyl)hydroxymethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethyl-1-naphthylmethyl)hydroxymethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethylphenyl)hydroxymethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid and

(1R,5S,6S)-2- (3S,5S)-5-(5-aminomethyl-2-fluorophenyl)hydroxymethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid.

Particularly preferred are (1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylthio)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-aminomethyl-2-sulfamoylphenyl)thiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylcarbamoyl)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylcarbamoyl)-2-sulfamoylphenyl!thiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-(3-aminopropionylamino)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylsulfonylamino)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-aminomethylphenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylsulfamoyl)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2-(3S,5S)-5-(8-aminomethyl-2-naphthylmethylthiomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5- 6-(4-carbamoylmethyl-1,4-diazobicyclo2.2.2!octanedium-1-ylmethyl)-2-naphthylmethylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethylphenylaminomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethylbenzyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,

(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethylphenyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid and

(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethylphenyl)hydroxymethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid.

The compounds of the formula I! have been created, as a result ofextensive researches by the present inventors, from compoundsrepresented by the formula: ##STR21## wherein R^(1c) is a hydrogen atomor a lower alkyl group, R^(2c) is a hydrogen atom or a negative charge,R^(3c) is a hydrogen atom or a lower alkyl group, Ar_(c) is a phenylgroup, a naphthyl group or a group of: ##STR22## (wherein each of A_(4c)and A_(5c), which may be the same or different, is a single bond, amethylene group, an oxygen atom, an imino group, a sulfur atom, asulfonyl group, --CONH-- or --NHSO₂ --, and Het^(c) is a pyrrolinylgroup, a pyrrolyl group, an imidazolyl group, an imidazolio group, apyrazolyl group, a thiazolyl group, a pyridyl group, a pyridinio group,a pyrazinyl group, a quinolyl group, an isoquinolyl group, apyrrolidinyl group, a piperidyl group, a piperazinyl group, amorpholinyl group, a benzothiazolyl group, an isoindolyl group, aquinuclidinyl group, a quinuclidinio group, abenzothiazol-1,1-dioxo-6-yl group or a 1,4-diazabicyclo 2.2.2!octanylgroup which may be substituted with the same or different one to threesubstituents selected from the group consisting of a hydroxyl group, ahalogen atom, a cyano group, a carboxyl group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a di-loweralkylcarbamoyl group, a carbamoyloxy group, an amino group, a loweralkylamino group, a di-lower alkylamino group, a tri-lower alkylammoniogroup, a formimidoylamino group, an acetimidoylamino group, a loweralkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, asulfo group, a sulfamoyl group, a lower alkylsulfamoyl group and adi-lower alkylsulfamoyl group) which may be substituted with the same ordifferent one to five substituents selected from the group consisting ofa lower alkyl group, a lower alkylcarbamoyl group, a lower alkylaminogroup, a lower alkoxy group, an aryloxy group, a lower alkylthio group,a lower alkylsulfonyl group and a lower alkylsulfamoyl group which maybe substituted with the same or different one to three substituentsselected from the group consisting of a hydroxyl group, a halogen atom,a cyano group, a carboxyl group, a lower alkoxycarbonyl group, acarbamoyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoylgroup, a carbamoyloxy group, an amino group, a lower alkylamino group, adi-lower alkylamino group, a tri-lower alkylammonio group, a carbamoyllower alkylamino group, an aroylamino group, an amino lower alkyl group,an amino lower alkylcarbonylamino group, a pyridyl group, apyridylcarbonylamino group, a pyridiniocarbonylamino group, aformimidoylamino group, an acetimidoylamino group, a lower alkoxy group,a lower alkylthio group, a sulfo group, an aminosulfonyl group, a loweralkylsulfonyl group and a di-lower alkylsulfonyl group, and a hydroxylgroup, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a di-lower alkylcarbamoylgroup, an arylcarbamoyl group, a piperazinocarbonyl group, an aminogroup, a di-lower alkylamino group, a tri-lower alkylammonio group, asulfamino group, a lower alkanoylamino group, an aralkylamino group, anaroylamino group, an arylsulfonylamino group, an amino loweralkylcarbonylamino group, a sulfamoyl group and a di-loweralkylsulfamoyl group, each of A_(1c), A_(2c) and A_(3c), which may besame or different, is a single bond or a lower alkylene group which maybe substituted with a substituent selected from the group consisting ofa lower alkyl group, a lower alkylcarbamoyl group, a lower alkylaminogroup, a lower alkoxy group, a lower alkylthio group, a loweralkylsulfonyl group, a lower alkylsulfonylamino group and a loweralkylsulfamoyl group which may be substituted with the same or differentone to three substituents selected from the group consisting of ahydroxyl group, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino group, alower alkylamino group, a di-lower alkylamino group, a tri-loweralkylammonio group, a formimidoylamino group, an acetimidoylamino group,a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonylgroup, a sulfo group, a sulfamoyl group, a lower alkylsulfamoyl groupand a di-lower alkylsulfamoyl group, and a pyridyl group (wherein thepyridyl group may be substituted with a substituent selected from thegroup consisting of a lower alkyl group, a carboxy lower alkyl group anda carbamoyl lower alkyl group), and W_(c) is a sulfur atom; compoundsrepresented by the formula: ##STR23## wherein R^(1d) is a hydrogen atomor a lower alkyl group, R^(2d) is a hydrogen atom, R^(3d) is a hydrogenatom or a lower alkyl group, each of R^(4d) and R^(5d), which may be thesame or different, is a hydrogen atom, a halogen atom, a hydroxyl group,a carbamoyl group or a sulfamoyl group, X_(d) is a hydrogen atom, alower alkyl group, a formyl group or a lower alkanoyl group, eitherY_(d) or Z_(d) is a hydrogen atom, the other is a group (d): ##STR24##(wherein each of R^(6d) and R^(7d), which may be the same or different,is a hydrogen atom or a lower alkyl group, or R^(6d) and R^(7d) form aC₂₋₆ alkylene group, and p_(d) is an integer of from 0 to 3), each ofA_(d) and B_(d), which may be the same or different, is a phenyl groupor a naphthyl group (provided that R^(5d), B_(d) and Z_(d) may form ahydrogen atom), m_(d) is 1 or 2, and n_(d) is 0 or 1 (provided that whenY_(d) or Z_(d) is a hydrogen atom, Z_(d) and R^(5d), or Y_(d) and R^(4d)may form a nitrogen-containing 5 to 7-membered heterocyclic ring);compounds represented by the formula: ##STR25## wherein R^(1e) is ahydrogen atom or a lower alkyl group, R^(2e) is a hydrogen atom, R^(3e)is a hydrogen atom or a lower alkyl group, each of R^(4e) and R^(5e),which may be the same or different, is a hydrogen atom, a carbamoylgroup or a sulfamoyl group, either Y_(e) or Z_(e) is a hydrogen atom,the other is a group (e): ##STR26## (wherein each of R^(6e) and R^(7e),which may be the same or different, is a hydrogen atom or a lower alkylgroup, or R^(6e) and R^(7e) form a C₂₋₆ alkylene group, and p_(e) is aninteger of from 0 to 3), each of A_(e) and B_(e), which may be the sameor different, is a phenyl group or a naphthyl group (provided thatR^(5e), B_(e) and Z_(e) may form a hydrogen atom), m_(e) is 1 or 2, andn_(e) is 0 or 1 (provided that when Y_(e) or Z_(e) is a hydrogen atom,Z_(e) and R^(5e), or Y_(e) and R^(4e) may form a nitrogen-containing 5to 7-membered heterocyclic ring); compounds represented by the formula:##STR27## wherein R^(1f) is a hydrogen atom or a lower alkyl group,R^(2f) is a hydrogen atom, R^(3f) is a hydrogen atom, a lower alkylgroup or a lower alkenyl group, each of R^(4f) and R^(5f), which may bethe same or different, is a hydrogen atom, a halogen atom, a hydroxylgroup, a lower alkyl group, a carbamoyl group or a sulfamoyl group,either Y_(f) or Z_(f) is a hydrogen atom, the other is a group (f):##STR28## (wherein each of R^(6f) and R^(7f) which may be the same ordifferent, is a hydrogen atom or a lower alkyl group, or R^(6f) andR^(7f) form a C₂₋₆ alkylene group, and p_(f) is an integer of from 0 to3), each of A_(f) and B_(f), which may be the same or different, is aphenyl group or a naphthyl group (provided that R^(5f), B_(f) and Z_(f)may form a hydrogen atom), and n_(f) is an integer of from 1 to 3(provided that when Y_(f) or Z_(f) is a hydrogen atom, Z_(f) and R^(5f),or Y_(f) and R^(4f) may form a nitrogen-containing 5 to 7-memberedheterocyclic ring); and compounds represented by the formula: ##STR29##wherein R^(1g) is a hydrogen atom or a lower alkyl group, R^(2g) is ahydrogen atom, R^(3g) is a hydrogen atom or a lower alkyl group, each ofR^(4g) and R^(5g), which may be the same or different, is a hydrogenatom, a halogen atom, a hydroxyl group, a lower alkyl group, a carbamoylgroup or a sulfamoyl group, either Y_(g) or Z_(g) is a hydrogen atom,the other is a group (g): ##STR30## (wherein each of R^(6g) and R^(7g),which may be the same or different, is a hydrogen atom or a lower alkylgroup, or R^(6g) and R^(7g) may form a C₂₋₆ alkylene group, and p_(g) isan integer of from 0 to 3), R^(8g) is a hydrogen atom, each of A_(g) andB_(g), which may be the same or different, is a phenyl group or anaphthyl group (provided that R^(5g), B_(g) and Z_(g) may form ahydrogen atom), m_(g) is an integer of 1 or 2, and n_(g) is an integerof 0 or 1 (provided that when Y_(g) or Z_(g) is a hydrogen atom, Z_(g)and R^(5g), or Y_(g) and R^(4g) may form a nitrogen-containing 5 to7-membered heterocyclic ring). The compounds of the formula I! naturallyinclude the compounds of the formula I-c!, the compounds of the formulaI-d!, the compounds of the formula I-e!, the compounds of the formulaI-f! and the compounds of the formula I-g!.

In the compounds of the formula I!, the mode of the substitution of thepyrrolidine ring in the side chain at the 2-position of the carbapenemstructure is not particularly restricted, and the pyrrolidine ring maybe substituted at any positions.

Therefore, the compounds of the formula I! include compounds of theformulae: ##STR31## wherein R¹, R², R³, Ar, A₁, A₂, A₃ and W are asdefined above. Particularly preferred are compounds of the formula I-s!.

The salt of the compound of the formula (I) is a common pharmaceuticallyacceptable salt and may, for example, be a salt at the carboxyl group atthe 3-position of the carbapenem structure, or at the pyrrolidine baseor the base on the side chain substituted on the pyrrolidine ring.

The basic addition salt at said carboxyl group includes, for example, analkali metal salt such as a sodium salt or a potassium salt; an alkalineearth metal salt such as a calcium salt or a magnesium salt; an ammoniumsalt; an aliphatic amine salt such as a trimethylamine salt, atriethylamine salt, a dicyclohexylamine salt, an ethanolamine salt, adiethanolamine salt, a triethanolamine salt or a procaine salt; anaralkylamine salt such as an N,N'-dibenzylethylenediamine salt; anaromatic heterocyclic amine salt such as a pyridine salt, a picolinesalt, a quinoline salt or an isoquinoline salt; a quaternary ammoniumsalt such as a tetramethylammonium salt, a tetraethylammonium salt, abenzyltrimethylammonium salt, a benzyltriethylammonium salt, abenzyltributylammonium salt, a methyltrioctylammonium salt or atetrabutylammonium salt; and a basic amino acid salt such as an argininesalt or a lysine salt.

The acid addition salt at the pyrrolidine base or at the base on theside chain substituted on the pyrrolidine ring includes, for example, aninorganic salt such as a hydrochloride, a sulfate, a nitrate, aphosphate, a carbonate, a hydrogencarbonate or a perchlorate; an organicsalt such as an acetate, a propionate, a lactate, a maleate, a fumarate,a tartrate, a malate, a succinate or an ascorbate; a sulfonate such as amethanesulfonate, an isethionate, a benzenesulfonate or ap-toluenesulfonate; and an acidic amino acid salt such as an aspartateor a glutamate.

The non-toxic ester of the compound of the formula (I) means a commonpharmaceutically acceptable ester at the carboxyl group at the3-position of the carbapenem structure. For example, it includes anester with an alkanoyloxymethyl group such as an acetoxymethyl group ora pivaloyloxymethyl group, an ester with an alkoxycarbonyloxyalkyl groupsuch as a 1-(ethoxycarbonyloxy)ethyl group, an ester with a phthalidylgroup and an ester with a (5-substituted-2-oxo-1,3-dioxol-4-yl)methylgroup such as a (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group.

Now, the process for producing the compound of the present inventionwill be described.

The compound of the formula I! can be obtained by reacting a compound ofthe formula: ##STR32## wherein R¹ is a hydrogen atom or a lower alkylgroup, R¹⁰ is a hydrogen atom or a hydroxyl-protecting group, and R²⁰ isa hydrogen atom or a carboxyl-protecting group, or a reactive derivativethereof, with a compound of the formula: ##STR33## wherein R³⁰ is ahydrogen atom, a lower alkyl group or an imino-protecting group, Ar₀ isa phenyl group, a naphthyl group or a group of: ##STR34## (wherein eachof A₄₀ and A₅₀, which may be the same or different, is a single bond, amethylene group, an ethylene group, an oxygen atom, an imino group whichmay be protected, a sulfur atom, a sulfonyl group, --CONH-- or --NHSO₂--, and Het⁰ is a pyrrolinyl group, a pyrrolyl group, an imidazolylgroup, an imidazolio group, a pyrazolyl group, a thiazolyl group, apyridyl group, a pyridinio group, a pyrazinyl group, a quinolyl group,an isoquinolyl group, a pyrrolidinyl group, a piperidyl group,piperazinyl group, a morpholinyl group, a benzothiazolyl group, anisoindolyl group, a quinuclidinyl group, a quinuclidinio group, abenzthiazol-1,1-dioxo-6-yl group or a 1,4-diazabicyclo 2.2.2!octanylgroup which may be substituted with the same or different one to threesubstituents selected from the group consisting of a hydroxyl groupwhich may be protected, a halogen atom, a cyano group, a carboxyl groupwhich may be protected, a lower alkoxycarbonyl group, a carbamoyl group,a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, acarbamoyloxy group, an amino group which may be protected, a loweralkylamino group, a di-lower alkylamino group, a tri-lower alkylammoniogroup, a formimidoylamino group, an acetimidoylamino group, a loweralkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, asulfo group, a sulfamoyl group, a lower alkylsulfamoyl group, a di-loweralkylsulfamoyl group, a lower alkyl group, a hydroxy lower alkyl groupwhich may be protected and a carbamoyl lower alkyl group) which may besubstituted with the same or different one to five substituents selectedfrom the group consisting of a lower alkyl group, a lower alkylcarbamoylgroup, a lower alkylsulfonylamino group, a lower alkylamino group, alower alkoxy group, an aryloxy group, a lower alkylthio group, a loweralkylsulfonyl group and a lower alkylsulfamoyl group which may besubstituted with the same or different one to three substituentsselected from the group consisting of a hydroxyl group which may beprotected, a halogen atom, a cyano group, a carboxyl group which may beprotected, a lower alkoxycarbonyl group, a carbamoyl group, a loweralkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxygroup, an amino group which may be protected, a lower alkylamino group,a di-lower alkylamino group, a tri-lower alkylammonio group, a carbamoyllower alkylamino group, an aroylamino group, an amino lower alkyl groupwhich may be protected, an amino lower alkylcarbonylamino group whichmay be protected, a pyridyl group, a pyridylcarbonylamino group, apyridiniocarbonylamino group, a formimidoylamino group, anacetimidoylamino group, a lower alkoxy group, a lower alkylthio group, asulfo group, an aminosulfonyl group, a lower alkylsulfonyl group and adi-lower alkylsulfonyl group, and a hydroxyl group which may beprotected, a halogen atom, a cyano group, a carboxyl group which may beprotected, a lower alkoxycarbonyl group, a carbamoyl group, a di-loweralkylcarbamoyl group, an arylcarbamoyl group, a piperazinocarbonylgroup, an amino group which may be protected, a di-lower alkylaminogroup, a tri-lower alkylammonio group, a sulfamino group, a loweralkanoylamino group, an aralkylamino group, an aroylamino group, anarylsulfonylamino group, an amino lower alkylcarbonylamino group whichmay be protected, a sulfamoyl group and a di-lower alkylsulfamoyl group,each of A₁₀, A₂₀ and A₃₀, which may be the same or different, is asingle bond or a lower alkylene group which may be substituted with asubstituent selected from the group consisting a lower alkyl group, alower alkylcarbamoyl group, a lower alkylamino group, a lower alkoxygroup, a lower alkylthio group, a lower alkylsulfonyl group, a loweralkylsulfonylamino group and a lower alkylsulfamoyl group which may besubstituted with the same or different one to three substituentsselected from the group consisting of a hydroxy group which may beprotected, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino groupwhich may be protected, a lower alkylamino group, a di-lower alkylaminogroup, a tri-lower alkylammonio group, a formimidoylamino group, anacetimidoylamino group, a lower alkoxy group, a lower alkylthio group, alower alkylsulfonyl group, a sulfo group, a sulfamoyl group, a loweralkylsulfamoyl group and a di-lower alkylsulfamoyl group, and a pyridylgroup and pyridinio group (wherein the pyridyl group and the pyridiniogroup may be substituted with a substituent selected from the groupconsisting of a lower alkyl group, a carboxy lower alkyl group which maybe protected and a carbamoyl lower alkyl group), and W₀ is a sulfuratom, a group of N--X₀ (wherein X₀ is a hydrogen atom, anamino-protecting group, a lower alkyl group, a formyl group, a loweralkanoyl group or a sulfamoyl group), an oxygen atom, a group of CH(OR⁸)(wherein R⁸ is a hydrogen atom or a hydroxyl-protecting group) or asingle bond, to obtain a compound of the formula: ##STR35## wherein R¹,R⁵, R²⁰, R³⁰, A₁₀, A₂₀, A₃₀, Ar₀ and W₀ are as defined above, then ifnecessary, removing any protecting groups of the compound of the formulaIV!, and if necessary, converting the compound thus obtained into apharmaceutically acceptable salt or non-toxic ester thereof.

A compound of the formula: ##STR36## wherein R¹, R¹⁰ and R²⁰ are asdefined above, is reacted with an activating reagent in an inert organicsolvent in the presence of a base to form a reactive derivative II'!represented by the formula: ##STR37## wherein R¹, R¹⁰ and R²⁰ are asdefined above, and L is a leaving group.

The inert organic solvent to be used for the reaction may, for example,be diethyl ether, tetrahydrofuran, dioxane, benzene, toluene,chlorobenzene, methylene chloride, chloroform, carbon tetrachloride,dichloroethane, trichloroethylene, acetone, ethyl acetate, acetonitrile,N,N-dimethylformamide, hexamethylphosphoric triamide or a mixture ofsuch solvents. Particularly preferred are acetonitrile and benzene.

The base to be used for the reaction may, for example, be a tertiaryaliphatic amine such as trimethylamine, triethylamine,N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine,N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo5.4.0!undec-7-ene (DBU) or 1,5-diazabicyclo 4.3.0!non-5-ene (DBN); or anaromatic amine such as pyridine, 4-dimethylaminopyridine, picoline,lutidine, guinoline or isoguinoline. Particularly preferred areN,N-diisopropylethylamine and triethylamine.

The activating reagent to be used for the reaction may, for example, bean acid anhydride such as trifluoroacetic anhydride, methanesulfonicanhydride, trifluoromethanesulfonic anhydride or p-toluenesulfonicanhydride; or an acid chloride such as methanesulfonyl chloride,p-toluenesulfonyl chloride or diphenyl chlorophosphate. Particularlypreferred is diphenyl chlorophosphate.

In the formula II'!, L is a leaving group such as a trifluoroacetoxygroup, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group,a p-toluenesulfonyloxy group or a diphenoxyphosphoryloxy group.Particularly preferred is a diphenoxyphosphoryloxy group.

For the reaction, from 1 to 3 mols, preferably from 1 to 1.5 mols, ofthe base and from 1 to 1.2 mols of the activating reagent are used permol of the compound of the formula II!.

The reaction is conducted usually within a temperature range of from-40° to 50° C., preferably from -20° to 20° C., and usually completedquantitatively in from 0.5 to 3 hours.

After completion of the reaction, the reaction product is treated inaccordance with a usual method to obtain the reactive derivative II'! ofthe compound of the formula II! quantitatively.

The reaction of the reactive derivative of the formula II'! with acompound of the formula: ##STR38## wherein R³⁰, Ar₀, A₁₀, A₂₀, A₃₀ andW₀ are as defined above, is conducted using the above-mentioned inertorganic solvent and base to form a compound of the formula: ##STR39##wherein R¹, R⁵, R²⁰, R³⁰, A₁₀, A₂₀, A₃₀, Ar₀ and W₀ are as definedabove.

The reaction is conducted using from 1 to 2 mols, preferably from 1 to1.5 mols, of the base and from 1 to 1.2 mols of the compound of theformula III!, per mol of the reactive derivative of the formula II'!.The reaction is conducted usually within a temperature range of from-40° to 50° C., preferably from -20° to 20° C., and the reaction iscompleted usually in from 0.5 to 3 hours.

Further, the compound of the formula IV! can be prepared in one stepfrom the compound of the formula II!. Namely, without isolating thereactive derivative of the formula II'! prepared from the compound ofthe formula II!, the compound of the formula III! is reacted thereto inthe same reaction system to prepare the compound of the formula IV!efficiently. To conduct the production in one step, from 2 to 4 mols,preferably from 2.5 to 3.5 mols, of the base is employed per mol of thecompound of the formula II!.

After completion of the reaction, usual treatment is conducted to obtaina crude product of the formula IV!, which may be subjected to a reactionfor removing a protecting group without purification. However, it ispreferred to purify the crude product IV! by crystallization or bycolumn chromatography by means of e.g. silica gel.

From the compound of the formula IV! thus obtained, a compound of theformula I! can be obtained, if necessary, by conducting a reaction forremoving a protecting group for a hydroxyl group, an amino group and acarboxyl group, and if necessary by converting the compound thusobtained into a pharmaceutically acceptable salt or non-toxic esterthereof.

For the removal of the protecting groups, the method varies dependingupon the type of the protecting groups. However, the removal can beconducted in accordance with conventional methods, for example, bysolvolysis, by chemical reduction or by hydrogenation.

For example, when in the above formula IV!, the protecting group for thehydroxyl group and/or for the amino group is an aralkyloxycarbonyl groupsuch as a benzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group,and the protecting group for the carboxyl group is an aralkyl group suchas a benzyl group, a p-nitrobenzyl group or a benzhydryl group, suchprotecting groups can be removed by catalytic hydrogenation by means ofa platinum catalyst such as platinum oxide, platinum wire or platinumblack, or a palladium catalyst such as palladium black, palladium oxide,palladium-carbon or palladium hydroxide-carbon.

As a solvent to be used for such a catalytic hydrogenation reaction,methanol, ethanol, tetrahydrofuran, dioxane, acetic acid or a solventmixture of such an organic solvent with water or with a buffer solutionof e.g. a phosphate, may be used.

The reaction can be completed in from 0.5 to 4 hours at a temperaturewithin a range of from 0° to 50° C. under hydrogen gas stream of from 1to 4 atm.

When in the above formula IV!, the protecting group for the hydroxylgroup and/or the amino group is an allyloxycarbonyl group, and theprotecting group for the carboxyl group is an allyl group, suchprotecting groups can be removed by reacting an organo-soluble palladiumcomplex catalyst in an inert organic solvent containing an allylgroup-capturing agent (method by W. McCombie et al., J. Org. Chem., vol.47, pp. 587-590 (1982) and method by F. Guibe et al., the sameliterature, vol. 52, pp. 4984-4993 (1987)).

The solvent useful for the reaction includes, for example, water,acetone, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate,acetonitrile, methylene chloride, chloroform and a solvent mixturethereof.

The palladium compound complex useful for this reaction includes, forexample, palladium-carbon, palladium hydroxide-carbon, palladium(II)chloride, palladium(II) acetate, tetrakis(triphenylphosphine)palladium(O), tetrakis(triphenoxyphosphine)palladium (O),tetrakis(triethoxyphosphine)palladium (O), bisethylenebis(diphenylphosphine)!palladium (O), tetrakistri(2-furyl)phosphine!palladium (O),bis(triphenylphosphine)palladium(II) chloride andbis(triphenylphosphine)palladium(II) acetate.

The allyl group-capturing agent may, for example, be dimedone, formicacid, acetic acid, ammonium formate, sodium formate, sodium2-ethylhexanoate, potassium 2-ethylhexanoate, pyrrolidine, piperidineand tributyltin hydride.

The reaction is conducted usually within a temperature range of from-10° to 50° C., preferably from 0° to 30° C. using from 0.01 to 0.5 molof the catalyst and from 1 to 6 mols of the nuclophilic agent relativeto 1 mol of the compound of the formula IV!, and the reaction iscompleted usually in from 0.5 to 3 hours.

Further, when in the above formula IV!, the protecting group for thehydroxyl group and/or the amino group is an o-nitrobenzyloxycarbonylgroup, and the protecting group for the carboxyl group is ano-nitrobenzyl group, such protecting groups can be removed by a photoreaction (method by Amit et al., J. Org. Chem., vol. 39, pp. 192-196(1974)).

After completion of the reactions for removing the protecting groups,the compound of the formula I! can be isolated by usual treatment suchas column chromatography using silica gel or adsorptive resin,freeze-drying or crystallization.

Further, when the protecting group for the carboxyl group at the3-position of the compound of the formula IV! is a loweralkanoyloxyalkyl group such as an acetoxymethyl group or apivaloyloxymethyl group, a methoxymethyl group, an indanyl group or aphthalidyl group, such an ester will be physiologically hydrolyzed invivo. Therefore, such a compound can directly be administered to a humanbeing or to an animal without preliminarily removing the protectinggroup.

The compound of the formula I! can be converted to a pharmaceuticallyacceptable salt or ester by a conventional method.

The starting material represented by the formula II! can be prepared,for example, by a method by Salzmann et al. when R¹ is a hydrogen atom(J. Am. Chem. Soc., vol. 102, pp.6161-6163 (1981)) or by a method byShih et al. when R¹ is a methyl group (Heterocycles, vol. 21, pp.29-40(1984)).

The starting material represented by the formula III! can be synthesizedin accordance with the methods described in the Reference Examples.

The compounds of the present invention exhibit strong antibacterialactivities against various gram positive bacteria including MRSA andgram negative bacteria.

To demonstrate the usefulness of the compounds of the present invention,the in vitro antibacterial activities against bacteria were measured bythe following agar plate dilution method (standard method by JapanChemotherapy Society, Chemotherapy, vol. 29, pp. 76-79 (1981)). Oneplatinum loopful of each test microorganism incubated overnight inMueller Hinton broth, was inoculated to Mueller Hinton agar (inoculumsize: 10⁶ CFU/ml). Such culture media contained antibacterial agents invarious concentrations. After incubation at 37° C. for 16 hours, theminimum inhibitory concentrations (MIC: μg/ml) were measured. Theminimum inhibitory concentrations of the compounds of the presentinvention were compared with imipenem. The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Minimum Inhibitory Concentration (MIC: μg/ml)                              Exam-       Exam-   Exam-   Exam- Exam-                                       ple 1       ple 121 ple 127 ple 131                                                                             ple 140                                                                             Imipenem                              ______________________________________                                        S. aureus                                                                             0.39    0.39    0.78  0.78  0.78  6.25                                BB5939*                                                                       S. aureus                                                                             1.56    1.56    3.13  3.13  1.56  >25                                 pMS520/                                                                       Smith                                                                         ______________________________________                                         *Latamase-producing bacterium                                            

Further, the DHP-I susceptibility was quantitatively analyzed by themethod by Kropp et al., Antimicrob. Agents Chemother., vol. 22, pp.62-70 (1982), whereby the smaller the numerical value representing theratio to imipenem (=1.0), the higher the stability.

The DHP-1 susceptibility of the compounds of the present invention werecompared with imipenem. The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        DHP-I Susceptibility                                                          Ex-       Ex-    Ex-    Ex-  Ex-  Ex-  Ex-                                    am-       am-    am-    am-  am-  am-  am-                                    ple       ple    ple    ple  ple  ple  ple                                    1         121    127    128  131  137  140  Imipenem                          ______________________________________                                        DHP-I  0.15   0.15   0.15 0.16 <0.05                                                                              <0.05                                                                              <0.05                                                                              1.0                             suscepti-                                                                     bility                                                                        ______________________________________                                    

The compounds of the present invention have excellent antibacterialactivities particularly, against gram positive bacteria including MRSAand are useful as antibacterial agents for the treatment and preventionof the human infectious diseases caused by such bacteria. Typicalpathogens sensitive to the antibacterial agents of the present inventioninclude, for example, species of genus Staphylococcus, genusEnterococcus, genus Escherichia, genus Enterobacter, genus Klebsiella,genus Serratia, genus Proteus and genus Pseudomonas.

The compounds of the present invention are markedly improved in sideeffects against the central nervous system and in the toxicity againstthe kidney, as compared with imipenem.

The compounds of the present invention are very stable against DHP-Ialthough the stability varies depending upon the individual compounds,and they are excellent also in the physicochemical stability and in thesolubility in water.

The compounds of the present invention may be used in the form of drugformulations suitable for parenteral administration, oral administrationor external administration, by mixing them with carriers of solid orliquid excipients known in this field. The main administration route isparenteral (intravenous or intramuscular injection) administration byinjection or local administration. Drug formulations include liquidformulations such as injection solutions, syrups or emulsions, solidformulations such as tablets, capsules or granules, and externalapplication formulations such as ointments or suppositories. Theseformulations may contain additives such as a base, an assisting agent, astabilizer, a wetting agent, an emulsifier, an absorption-promotingagent, a surfactant, etc. which are commonly employed, as the caserequires.

The additives include, for example, distilled water for injection,Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cacaobutter, ethylene glycol, sucrose, corn starch, magnesium stearate andtalc.

The dose varies depending upon the condition, the weight, the age andthe sex of the patient, the type of formulation, the number ofadministration times, etc. Usually, however, a preferred daily dose ofthe active ingredient to an adult is from about 5 to 50 mg/kg, and apreferred daily dose to a child is within a range of from about 5 to 25mg/kg, which is preferably administered once a day or in a few times aday.

The compound of the present invention may be administered in combinationwith a DEP-I inhibiting agent such as cilastatin sodium(Z)-7-(L-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoate!(Japanese Unexamined Patent Publication No. 81518/1981; European PatentNo. 28,778; J. Med. Chem., vol. 30, p. 1074 (1987)).

EXAMPLES AND REFERENCE EXAMPLES

The present invention is now illustrated in greater detail by way ofEXAMPLES and REFERENCE EXAMPLES, but it should not be understood thatthe present invention is deemed to be limited thereto.

In Examples and Reference Examples, for thin layer chromatography,Silicagel 60F₂₄₅ (Merck) was used as plates, and a UV detector was usedas a means for detection. Silica gel for column chromatography usedherein was Wakogel™ C-300 (Wakojunyaku), and the silica gel for reversephase column chromatography was LC-SORB™ SP-B-ODS (Chemco) or YMC-GEL™ODS-AQ120-S50 (Yamamura Kagaku Kenkyujo). As the high pressure liquidchromatography, JASCO 800 series (Japan Spectroscopic Co., Ltd.) wasused. When the NMR spectrum was measured using dimethyl sulfoxide-d₆ orchloroform-d solution, tetramethylsilane (TMS) was used as the internalstandard, and when measured using a deuterium oxide solution,2,2-dimethyl-2-silapentane-5-sulfonate (DSS) was used as the internalstandard, and the measurement was conducted by means of XL-200 (200 MHz;Varian) model spectrometer. All δ values are shown by ppm.

The meanings of the abbreviations used for the NMR measurement are asfollows:

s: singlet

d: doublet

dd: double doublet

m: multiplet

br: broad

J: coupling constant

Hz: hertz

CDCl₃ : chloroform-d

D₂ O: deuterium oxide

Abbreviations used in reaction schemes have the following meanings.

Ac: acetyl group

All: allyl group

Alloc: allyloxycarbonyl group

^(t) Bu: t-butyl group

Boc: t-butoxycarbonyl group

Me: methyl group

Ms: methanesulfonyl group (mesyl group)

MOM: methoxymethoxy group

Ph: phenyl group

PNB: p-nitrobenzyl group

PNZ: p-nitrobenzyloxycarbonyl group

Tr: trityl group

TBS: t-butyldimethylsilyl group

TBDPS: t-butyldiphenylsilyl group

THP: tetrahydropyranyl group

EXAMPLE 1

Sodium (1R,5S,6S)-6- (1R)-1-hydroxyethyl!-1-methyl-2-(3S,5S)-5-(phenylthiomethyl)pyrrolidin-3-ylthio!-1-carbapen-2-em-3-carboxylate##STR40## (Step 1)

To a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate (2.24 g,3.78 mmol) in acetonitrile (70 ml), DIPA (0.9 ml, 5.16 mmol) was addedunder cooling with ice, and then a solution of(3S,5S)-3-mercapto-1-p-nitrobenzyloxycarbonyl-5-(phenylthiomethyl)pyrrolidine(1.39 g, 3.42 mmol) in acetonitrile (15 ml) was dropwise added thereto.The reaction solution was stirred at 5° C. overnight, and ethyl acetate(300 ml) was added to the reaction solution. The organic layer waswashed with water and saturated aqueous sodium chloride, dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography (dichloromethane-ethylacetate), to give p-nitrobenzyl (1R,5S,6S)-6-(1R)-1-hydroxyethyl!-1-methyl-2-(3S,5S)-1-p-nitrobenzyloxycarbonyl-5-(phenylthiomethyl)pyrrolidin-3-ylthio!-1-carbapen-2-em-3-carboxylate(1.55 g, yield: 60%).

IR(KBr)cm³¹ 1 : 3469,2969,1770,1704,1606,1519,1346,1209, 1139,852,738.

¹ H-NMR(CDCl₃)δ:1.24(3H,d,J=7.4 Hz),1.36(3H,d,J=6.0 Hz),2.50-2.70(1H,m),2.90-3.20(1H,m),3.20-3.70(5H,m),4.10-4.30(4H,m),5.10-5.30(3H,m),5.50-5.60(1H,m),7.20-7.30(6H,m),7.40-7.50(3H,m),7.60-7.70(2H,m),8.10-8.30(4H,m)

(Step 2)

To a solution of the compound (1.29 g, 1.70 mmol) obtained in Step 1 ina mixture of 0.2M MOPS buffer (pH 7.0, 45 ml), THF (45 ml) and ethanol(9 ml), 10% palladium-carbon (1.3 g) was added, and catalytic reductionwas conducted at room temperature under a pressure of 3 atom of hydrogenfor 8 hours. The catalyst was filtered off, and the filtrate wasconcentrated in vacuo. The resulting aqueous solution was adjusted to pH8 with aqueous sodium hydrogencarbonate, washed with ethyl acetate andconcentrated in vacuo. The insolubles formed in small amounts werefiltered off, and the filtrate was purified by reverse phase columnchromatography (eluted with 50 ml of 15% water-containing THF). Thedesired fractions were Collected, and the solvent was removed in vacuo,and the residue was lyophilized to give the title compound (96 mg,yield: 12%).

IR(KBr)cm⁻¹ : 3415,2965,1750,1590,1390,1285,1145,1085, 745,605.

¹ H-NMR(D₂ O)δ:1.17(3H,d,J=7.3 Hz),1.27(3H,d,J=6.3 Hz),1.50-1.70(1H,m),2.50-2.70(1H,m),3.10-3.50(7H,m),3.50-3.60(1H,m),3.80-3.90(1H,m),4.10-4.30(2H,m),4.80(1H,s),7.30-7.50(6H,m).

UVλ_(max) (0.1M MOPS buffer, pH7.0): 297 nm (ε=6470).

EXAMPLE 2

Sodium (1R,5S,6S)-6- (1R)-1-hydroxyethyl!-1-methyl-2-(3S,5S)-5-(4-sulfonamidephenylthiomethyl)pyrrolidin-3-ylthio!-1-carbapen-2-em-3-carboxylate##STR41## (Step 1)

To a solution of(2S,4S)-4-acetylthio-1-p-nitrobenzyloxycarbonyl-2-(4-sulfamoylphenyl)thiomethylpyrrolidine(1.48 g, 2.82 mmol) in a mixture of methanol (30 ml) with chloroform (30ml), 1N aqueous NaOH (3.11 ml, 3.11 mmol) was added in a nitrogen streamat 5° C., and the resulting reaction solution was stirred at the sametemperature for 1 hour. The reaction solution was neutralized with 1Naqueous HCl (3.11 ml, 3.11 mmol), and the solvent was distilled off invacuo. To a solution of the residue and p-nitrobenzyl(1R,5S,6S)-2-diphenylphosphoryloxy-6-(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate (2.24 g,3.78 mmol) in acetonitrile (50 ml), DIPA (0.78 ml, 4.48 mmol) was added,and the reaction solution was stirred at 5° C. overnight. To thereaction solution, ethyl acetate was added. The solution was washedsuccessively with water, 10% aqueous citric acid, saturated aqueoussodium hydrogencarbonate and saturated aqueous sodium chloride. Then, itwas dried over anhydrous sodium sulfate, and the solvent was distilledoff in vacuo. The resulting residue was purified by silica gel columnchromatography (heptane-ethyl acetate) to give p-nitrobenzyl(1R,5S,6S)-6- (1R)-1-hydroxyethyl!-1-methyl-2-(3S,5S)-1-p-nitrobenzyloxycarbonyl-5-(4-sulfamoylphenylthiomethyl)pyrrolidin-3-ylthio)-1-carbapen-2-em-3-carboxylate(1.57 g, yield: 67%).

IR(KBr)cm⁻¹ : 3392,1770,1699,1606,1519,1346,1209, 1162,1139,1106.

¹ H-NMR(DMSO-d₆)δ: 1.14(6H,d,J=7.1 Hz),1.75-1.94(1H,m),2.44-2.74(1H,m),3.00-3.70(5H,m),3.88-4.30(5H,m), 5.07(1H,d,J=5.3Hz),5.15-5.53(1H,m),7.32(2H,br s),7.35-7.77(8H,m),8.22(4H,d,J=8.6 Hz).

(Step 2)

To a solution of the compound (0.5 g, 0.62 mmol) obtained in Step 1 in amixture of 0.5M MOPS buffer (pH 7.0, 9.8 mol), THF (27 ml) and ethanol(14 ml), 10% palladium-carbon (0.50 g) was added and catalytic reductionwas conducted at room temperature at an ordinary temperature under theatmospheric pressure of hydrogen overnight. The catalyst was filteredoff, and the filtrated was concentrated in vacuo. The resulting aqueoussolution was washed with methylene chloride and then concentrated again.The insolubles formed in small amounts were filtered off and thefiltrate was purified by reverse phase column chromatography (elutedwith 50 ml of 6-12% water-containing THF). The desired fractions werecollected, the solvent was distilled off, and then the residue waslyophilized to give the title compound (21 mg, yield: 64%).

IR(KBr)cm⁻¹ : 3382,2967,1745,1589,1392,1326,1159,1079,923.

¹ H-NMR(D₂ O)δ: 1.13(3H,d,J=7.2 Hz),1.24(3H,d,J=6.4Hz),1.40-1.55(1H,m),2.45-2.63(1H,m),2.93-3.04(1H,m),3.17-3.56(6H,m),3.67-3.83(1H,m),4.08-4.26(2H,m),7.51(2H,dd,J=2.1&6.8 Hz),7.78(2H,dd,J=2.1&6.8 Hz).

UVλ_(max) (0.1M MOPS buffer, pH7.0):300 nm (ε=10800).

EXAMPLE 3

(1R,5S,6S)-2- (3S,5S)-5-4-(2-Aminoethylthio)-phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acidmonohydrochloride ##STR42## (Step 1)

To a solution of (2S,4S)-4-tritylthio-1-(4-allyloxycarbonyl)-2-4-(2-allyloxycarbonylaminoethylthio)phenylthiomethyl!-pyrrolidine (1.53g, 2.14 mmol) in methylene chloride (30 ml), triethylsilane (0.41 ml)and trifluoroacetic acid (5 ml) were added at 5° C., and the resultingreaction solution was stirred at the same temperature for 1 hour. Thesolvent was distilled off in vacuo, and the resulting residue wasdissolved in ethyl acetate. The organic layer was washed successivelywith water, phosphate buffer (pH 5.5) and saturated aqueous sodiumchloride and dried over anhydrous sodium sulfate, and the solvent wasdistilled off in vacuo. The resulting residue was purified by silica gelcolumn chromatography (ethyl acetate-heptane) to give 0.71 g of an oilythiol derivative. To a solution of the thiol derivative and ally(1R,5S,6S)-2-diphenylphosphoryloxy-6-(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate (756 mg,1.52 mmol) in acetonitrile (28 ml), DIPA (0.317 ml, 1.80 mmol) was addedunder cooling with ice, and the reaction solution was stirred at 5° C.overnight. To the reaction solution, ethyl acetate (100 ml) was added,and the resulting mixture was washed successively with water andsaturated aqueous sodium chloride. The organic layer was dried overanhydrous sodium sulfate, and the solvent was distilled off in vacuo.The resulting residue was purified by silica gel column chromatography(heptane-ethyl acetate) to give allyl (1R,5S,6S)-2-(3S,5S)-1-N-(allyloxycarbonyl)-5-4-(2-aminoethylthio)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate (590 mg,yield: 54%).

IR(KBr)cm⁻¹ : 3390,2960,1770,1704,1540,1405,1324,1274,1207,1139,1106,1045,983,933,813,769,719.

¹ H-NMR(CDCl₃)δ: 1.24(3H,d,J=5.1 Hz), 1.35(3H,d,J=6.3 Hz),1.99(1H,m),2.56(1H,m),3.02(3H,m),3.20-3.40(5H,m),3.58(2H,m),3.90-4.30(4H,m),4.60-4.90(2H,m),5.10-5.50(7H,m),5.80-6.10(3H,m),7.29(4H,s).

(Step 2)

To a solution of the compound (590 mg, 0.82 mmol) obtained in Step 1 inmethylene chloride (15 ml), water (0.1 ml),bis(triphenylphosphine)palladium(II) chloride (21 mg, 0.03 mmol) andtributyltin hydride (1.1 ml, 4.1 mmol) were added in a nitrogen streamunder cooling with ice. The resulting mixture was stirred at the sametemperature for 30 minutes and then extracted with phosphate buffer(0.3M, pH 5.6, 100 ml×3). The extract was concentrated in vacuo,adjusted to pH 8.9 with 1N aqueous NaOH, and purified by reverse phasechromatography (eluted with 14 ml of 4-15% water-containing THF). Thedesired fractions were collected, adjusted to pH 6.6 with 1N HCl, andthen concentrated in vacuo. The residue was lyophilized to give thetitle compound (211 mg, yield: 47%).

IR(KBr)cm⁻¹ : 3384,2967,1751,1581,1392,1286,1265,1182, 1149,1105,813.

¹ H-NMR(D₂ O)δ: 1.18(3H,d,J=7.2 Hz),1.28(3H,d,J=6.3 Hz),1.69(1H,m),2.69(1H,m),3.15-3.65(10H,m),3.80(1H,m),3.95(1H,m),4.25(2H,m),7.48(4H,s).

UVλ_(max) (0.1M MOPS buffer, pH 7.0):300 nm (ε=10700).

EXAMPLE 4

(1R,5S,6S)-2-(3S,5S)-5-(3-Aminomethyl-4-chlorophenylthiomethyl)pyrrolidin-3-ylthio!-6-(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid##STR43## (Step 1)

To a mixed solution of(2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(3-allyloxycarbonylaminomethyl-4-chlorophenyl)thiomethylpyrrolidine(481 mg, 0.87 mmol) in a mixture of methanol (4 ml) and THF (2 ml), 1Naqueous NaOH (0.95 ml, 0.95 mmol) was added in a nitrogen stream. Thereaction solution was stirred at the same temperature for 20 minutes.The mixture was neutralized with 1N aqueous HCl (1.04 ml, 1.04 mmol) andthen ethyl acetate and water were added thereto. The organic layer waswashed successively with water and saturated aqueous sodium chloride.The solvent was distilled off in vacuo to obtain a crude thiolderivative. To a solution of allyl(1R,5S,6S)-2-diphenoxyphosphoryloxy-6-(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate (478 mg,0.96 mmol) in acetonitrile (7 ml), a solution of the thiol derivativeobtained as above in acetonitrile (7 ml) and DIPA (0.227 ml, 1.31 mmol)were added in a nitrogen stream. The reaction solution was stirred at atemperature from -20° C. to -30° C. overnight. To the reaction solution,ethyl acetate was added and the organic layer was washed successivelywith water and saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and then concentrated in vacuo. The resulting residuewas purified by silica gel column chromatography (heptane-ethyl acetate)to give allyl (1R,5S,6S)-6- (1R)-1-hydroxyethyl!-2-(3S,5S)-1-allyloxycarbonyl-5-(3-allyloxycarbonylaminoethyl-4-chlorophenyl)thiomethylpyrrolidin-3-ylthio!-1-methyl-carbapen-2-em-3-carboxylate(242 mg, yield: 39.4%).

IR(KBr)cm⁻¹ : 3420,1693,1549,1408,1340,1107,797,606.

¹ H-NMR(CDCl₃)δ: 1.20-1.30(3H,m),1.40-1.50(3H,m),1.90-2.10(1H,m),2.50-2.60(1H,m),3.20-4.30(9H,m),4.40-4.60(8H,m),5.20-5.50(6H,m),5.81-6.10(3H,m),7.20-7.40(3H,m).

(Step 2)

To a solution of the compound (242 mg, 0.34 mmol) obtained in Step 1 inmethylene chloride (6 ml), water (0.03 ml),bis(triphenylphosphine)palladium(II) chloride (4.8 mg, 0.0068 mmol) andtributyltin hydride (0.302 ml, 1.12 mmol) were added in a nitrogenstream under cooling with ice. The resulting mixture was stirred at 0°C. for 10 minutes and then at room temperature for 30 minutes. Thesolvent was distilled off in vacuo and the residue was dissolved in 1Naqueous sodium hydrogencarbonate. The resulting solution was washed withheptane three times, concentrated in vacuo and then purified by reversephase column chromatography (eluted with 14 ml of 9-15% water-containingtetrahydrofuran). The desired fractions were collected and the solventwas distilled off in vacuo. The resulting residue was lyophilized togive the title compound (84 mg, yield: 50%).

IR(KBr)cm⁻¹ : 3417,2968,1745,1585,1392,1281,1103,1047, 770,606.

¹ H-NMR(D₂ O)δ: 1.18(3H,d,J=7.0 Hz), 1.28(3H,d,J=6.3 Hz),1.60-1.70(1H,m),2.60-2.70(1H,m),3.20-3.50(7H,m),3.70-3.80(1H,m),3.80-3.90(1H,m),4.20-4.30(3H,m),7.50-7.60(3H,m).

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm (ε=7950).

EXAMPLE 5

(1R,5S,6S)-2- (3S,5S)-5-(4-Aminomethyl-2-sulfamoyl)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-1-hydroxyethyl!-1-methyl-carbapen-2-em-3-carboxylic acidmonohydrochloride ##STR44## (Step 1)

To a solution of (2S,4S)-4-acetyltylthio-2-(4-p-nitrobenzyloxycarbonylaminomethyl-2-sulfamoyl)phenylthiomethyl!-1-p-nitrobenzyloxycarbonylpyrrolidin(540 mg, 0.74 mmol) in methanol (10 ml) and THF (2 ml), 1N aqueous NaOH(0.809 ml, 0.81 mmol) was added at 0° C. in a nitrogen stream and theresulting reaction solution was stirred at the same temperature for 45minutes. The reaction solution was neutralized with 1N aqueous HCl(0.883 ml, 0.88 mmol) and then ethyl acetate was added thereto. Theorganic layer was washed with water and concentrated in vacuo. To asolution of the resulting residue and p-nitrobenzyl(1R,5S,6S)-2-diphenylphosphoryloxy-6-(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate (438 mg,0.74 mmol) in acetonitrile (16 ml), DIPA (0.192 ml, 1.1 mmol) was added.The resulting reaction solution was stirred at 5° C. overnight. To thereaction solution, ethyl acetate was added, and the organic layer waswashed successively with water, 10% aqueous citric acid, saturatedaqueous sodium hydrogencarbonate, and saturated aqueous sodiumchloride.. After drying over anhydrous sodium sulfate, the solvent wasdistilled off in vacuo. The resulting residue was purified by silica gelcolumn chromatography (chloroform-methanol) to give p-nitrobenzyl(1R,5S,6S)-2- (3S,5S)-5-(4-p-nitrogenzyloxycarbonylaminomethyl-2-sulfamoyl)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate (190 mg,yield: 25%).

IR(KBr)cm⁻¹ : 3396,1768,1702,1521,1346,1110.

(Step 2)

A solution of the compound (250 mg, 0.24 mmol) obtained in Step 1 wasdissolved in a mixture of 0.2M MOPS buffer (pH 7.0, 6 ml), THF (6 ml)and ethanol (1.2 mmol). To the mixture, 10% palladium-carbon (0.2 g) wasadded and catalytic reduction was conducted at room temperature underthe atmospheric pressure of hydrogen overnight. The catalyst wasfiltered off, then the filtrate was concentrated in vacuo, and theresulting aqueous solution was washed with chloroform and concentratedagain. The insolubles formed in small amounts were filtered off, and thefiltrate was purified by reverse phase column chromatography (elutedwith 14 ml of 6-9% water-containing THF). The fractions containing thedesired product were collected, adjusted to pH 6.2 with hydrochloricacid, concentrated in vacuo and lyophilized to give the title compound(66 mg, yield: 48%).

IR(KBr)cm⁻¹ : 3386,2968,1749,1579,1392,1331,1157.

¹ H-NMR(D₂ O)δ: 1.13(3H,d,J=7.3 Hz), 1.22(3H,d,J=6.4 Hz),1.73(1H,m),2.70(1H,m),3.25-3.45(3H,m),3.45-3.70(3H,m),3.85-4.05(2H,m),4.10-4.30,4.68,7.67(1H,d,J=8.0 Hz),7.77(1H,d,J=8.0 Hz),8.06(1H,s).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=12200).

In the following Examples 6 to 64, compounds represented by the formula(A) which have substituents R₁ and R₂ were synthesized in the samemanner as in Examples 1 to5. ##STR45##

EXAMPLE 6 ##STR46##

IR(KBr)cm⁻¹ : 3430,2970,1750,1590,1400,1290,1140,1090,740.

¹ H-NMR(D₂ O)δ: 1.16(3H,d,J=7.0 Hz), 1.25(3H,d,J=6.0 Hz),1.80-2.00(2H,m),2.40(1H,m),2.80-3.40(8H,m),3.70(1H,m),4.10-4.30(2H,m),7.20-7.50(5H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=7310).

EXAMPLE 7 ##STR47##

IR(KBr)cm⁻¹ : 3425,1750,1595,1395,1290,1080.

¹ H-NMR(D₂ O)δ: 1.18(3H,d,J=7.2 Hz), 1.28(3H,d,J=6.4Hz),2.40-2.50(2H,m),2.60-2.70(2H,m),2.80-2.90(1H,m),3.00-3.50(4H,m),3.60-3.90(3H,m),4.10-4.30(2H,m),7.30-7.50(5H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=7330).

EXAMPLE 8 ##STR48##

IR(KBr)cm⁻¹ : 3438,1745,1670,1620,1350.

¹ H-NMR(D₂ O)δ: 1.19(3H,d,J=7.0 Hz), 1.28(3H,d,J=6.2 Hz),1.58(3H,d,J=7.0 Hz),2.40-2.90(4H,m),3.00-3.10(1H,m),3.20-3.50(4H,m),3.70-3.90(1H,m),4.10-4.30 (3H,m),7.30-7.60(5H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 298 nm (ε=5500).

EXAMPLE 9 ##STR49##

IR(KBr)cm⁻¹ : 3425,2965,1755,1590,1390,775,605.

¹ H-NMR(D₂ O)δ: 0.80-1.10(2H,m), 1.18(3H,d,J=7.1 Hz), 1.28(3H,d,J=6.3Hz),1.50-1.70(1H,m),2.32(3H,s),2.50-2.70(1H,m),3.00-3.50(6H,m),3.50-3.60(1H,m),3.80-3.90(1H,m),4.10-4.30(2H,m),4.60-5.00(1H,m),7.10-7.20(1H,m),7.20-7.40(1H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 298 nm (ε=8880).

EXAMPLE 10 ##STR50##

IR(KBr)cm⁻¹ : 3425,2964,1755,1597,1392,1266,1076,609.

¹ H-NMR(D₂ O)δ: 1.14(3H,d,J=7.4 Hz), 1.24(9H,s), 1.26(3H,d,J=9.3 Hz),1.40(1H,m),2.40(1H,m),2.90(1H,m),3,10-3,40(6H,m),3.63(1H,m),4.22(2H,m),7.38(4H,s).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 296 nm (ε=8000).

EXAMPLE 11 ##STR51##

IR(KBr)cm⁻¹ : 3432,2967,2358,1753,1593,1452,1392,1255.

¹ H-NMR(D₂ O) δ: 1.21(3H,d,J=7.1 Hz), 1.31(3H,d,J=6.4 Hz),1.47(1H,m),2.55(1H,m),2.98(1H,m),3.20-3.50(6H,m),3.78(1H,m),4.22(2H,m),6.95(1H,m),7.22(1H,m),7.62(1H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=8780).

EXAMPLE 12 ##STR52##

IR(KBr)cm⁻¹ : 3421,1749,1592,1452,1398,1284.

¹ H-NMR(D₂ O)δ: 0.90-1.40(1H,m), 1.05(3H,d,J=6.7 Hz), 1.21(3H,d,J=6.2Hz),2.26-2.47(1H,m),2.86-2.91(1H,m),2.96-3.32(6H,m),3.43-3.61(1H,m),4.03-4.25(2H,m),7.04-7.46(4H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=8100).

EXAMPLE 13 ##STR53##

IR(KRr)cm⁻¹ : 3425,1750,1595,1400,1085,610.

¹ H-NMR(D₂ O)δ: 1.17(3H,d,J=7.5 Hz),1.27(3H,d,J=6.1 Hz),2.30-2.50(1H,m),2.80-3.00(1H,m),3.00-3.50(6H,m),3.60-3.70(1H,m),4.20-4.40(2H,m),7.35(2H,d,J=8.7Hz), 7.52(2H,d,J=8.7 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=6810).

EXAMPLE 14 ##STR54##

IR(KBr)cm⁻¹ : 3420,2970,1750,1650,1600,1520,1400,1310,1180, 780.

¹ H-NMR(D₂ O)δ: 1.19(3H,d,J=7.0 Hz), 1.25(3H,d,J=6.0 Hz),1.90(1H,m),2.50-2.80(3H,m),3.00-3.30(2H,m),3.40(1H,m),3.50-3.80(2H,m),3.90(1H,m),4.10-4.30(2H,m),5.55(1,m),6.50(1H,m),7.20(1H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 297 nm (ε=9840).

EXAMPLE 15 ##STR55##

IR(KBr)cm⁻¹ : 3430,2970,1750,1590,1490,1400,1280,1250,1080, 830,610.

¹ H-NMR(D₂ O)δ: 1.13(3H,d,J=7.0 Hz), 1.25(3H,d,J=6.0 Hz),2.40(1H,m),2.85(1H,m),3.00-3.40(6H,m),3.65(1H,m),3.79(3H,s),4.10-4.30(2H,m),6.96(2H,d,J=9.0Hz),7.44(2H,d,J=9.0 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=8110).

EXAMPLE 16 ##STR56##

IR(KBr)cm⁻¹ : 1747,1737,1649,1591,1560,1543,1398,1290.

¹ H-NMR(D₂ O)δ: 1.13(3H,d,J=7.0 Hz), 1.23(3H,d,J=6.5 Hz),1.62(1H,m),2.60(1H,m),3.00-3.34(4H,m),3.40(1H,m),3.50(1H,m),3.62(1H,m),3.88(1H,m),4.10-4.24(2H,m), 6.76(1H,d,J=7.4Hz),7.22(1H,dd,J=1.6&7.4 Hz), 7.47(1H,d,J=1.6 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 296 nm (ε=7900).

EXAMPLE 17 ##STR57##

IR(KBr)cm⁻¹ : 3419,1747,1593,1394,1282,1101,1065,770,606.

¹ H-NMR(D₂ O)δ: 1.18(3H,d,J=7.3 Hz), 1.28(3H,d,J=6.4 Hz),1.60-1.70(1H,m),2.60-2.70(1H,m),3.20-3.60(6H,m),3.70-3.80(1H,m),3.90-4.00(1H,m),4.20-4.30(2H,m),7.40-7.60(3H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=8130).

EXAMPLE 18 ##STR58##

IR(KBr)cm⁻¹ : 3421,3388,1751,1587,1567,1394.

¹ H-NMR(D₂ O)δ: 1.23(3H,d,J=7.3 Hz), 1.32(3H,d,J=6.4 Hz),1.76-1.82(1H,m),2.72-2.77(1H,m),3.32-3.66(6H,m),3.82-3.85(1H,m),3.98-4.03(1H,m),4.23-4.32(2H,m),7.43-7.67(4H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 297 nm (ε=9360).

EXAMPLE 19 ##STR59##

IR(KBr)cm⁻¹ : 3419,2967,1751,1594,1479,1394,1286,1106,811.

¹ H-NMR(D₂ O)δ: 1.11(3H,d,J=7.1 Hz), 1.27(3H,d,J=6.2 Hz),1.28(1H,m),2.35(1H,m),2.40(3H,s),2.85(1H,m),3.00-3.30(5H,m),3.34(1H,dd,J=2.2&6.0Hz),3.56(1H,m),4.20(2H, m),7.17(2H,d,J=8.5 Hz),7.35(2H,d,J=8.5 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=10800).

EXAMPLE 20 ##STR60##

IR(KBr)cm⁻¹ : 3417,1745,1662,1591,1396,1290,1105,606.

¹ H-NMR(D₂ O)δ: 1.18(3H,d,J=7.1 Hz), 1.29(3H,d,J=6.4 Hz),1.30-1.40(1H,m),2.41-2.50(1H,m),2.80-3.00(1H,m),3.10-3.50(6H,m),3.70-3.80(1H,m),4.10-4.30(2H,m),7.50-7.60(3H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 297 nm (ε=10300).

EXAMPLE 21 ##STR61##

IR(KBr)cm⁻¹ : 3421,2966,1765,1639,1593,1549,1396,1317,1147,1092,762,606.

¹ H-NMR(D₂ O)δ: 1.15(3H,d,J=4.9 Hz), 1.25(3H,d,J=6.3 Hz),1.60-1.80(1H,m),2.60-2.80(1H,m),2.90(3H,s),3.20-3.60(5H,m),3.70-3.80(1H,m),4.00-4.90(1H,m),4.15-4.30(2H,m),7.49(2H,d,J=5.6Hz),7.68(2H,d,J=6.0 Hz)

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=12600).

EXAMPLE 22 ##STR62##

IR(KBr)cm⁻¹ : 419,1747,1603,1396,1267,1099,763,606.

¹ H-NMR(D₂ O)δ: 1.18(3H,d,J=7.1 Hz), 1.27(3H,d,J=6.4 Hz),1.70-1.80(1H,m),2.60-2.80(1H,m),3.00(3H,s),3,08(3H,s),3.30-3.40(3H,m),3.40-3.50(1H,m),3.50-3.60(2H,m),3.70-3.80(1H,m),3.90-4.00(1H,m),4.20-4.40(2H,m),7.41 (2H,d,J=8.3Hz),7.54(2H,d,J=8.3 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=9630).

EXAMPLE 23 ##STR63##

IR(KBr)cm⁻¹ : 3394,2968,1045,1660,1593,1394,1282,1146,1088, 804,770,606.

¹ H-NMR(D₂ O)δ: 1.17(3H,d,J=7.4 Hz), 1.27(3H,d,J=6.4 Hz),1.70-1.80(1H,m),2.70-2.80(1H,m),3.20-3.70(8H,m),3.70-3.80(1H,m),3.90-4.00(1H,m),4.20-4.30(2H,m),7.30(2H,d,J=8.1 Hz),7.47(2H,d,J=6.2 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=8190).

EXAMPLE 24 ##STR64##

IR(KBr) cm⁻¹ : 3743,3490,1751,1743,1706,1597,1463,1394,1286.

¹ H-NMR(D₂ O)δ: 1.08 (3H,d,J=7.0 Hz) ,1.17 (3H,d,J=6.4 Hz ), 1.50-1.60(1H,m), 2.50-2.65 (1H,m), 2.90-3.87 (23H,m), 4.05-4.20(2H,m),7.33(2H,d,J=8.3 Hz),7.45(2H,d,J=8.3 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=9940).

EXAMPLE 25 ##STR65##

IR(KBr)cm⁻² : 3394,2968,1745,1670,1595,1398,1290,1103,606.

¹ H-NMR(D₂ O)δ: 1.19 (3H, d, J=7.1 Hz ), 1.28 (3H, d,J=6.4 Hz ),1.40-1.50 (1H,m), 2.41-2.60 (1H).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 299 nm (ε=10300).

EXAMPLE 26 ##STR66##

IR(KBr)cm⁻¹ : 3453,1741,1646,1596,1538,1394,1344.

¹ H-NMR(D₂ O)δ: 1.20 (3H,d,J=7.0 Hz), 1.27 (4H, d,J=4.8 Hz),1.80-2.00(1H,m),2.30-2.60(3H,m),2.80-3.00(2H,m),3.00-3.40(4H,m),3.70-3.80(2H,m),4.10-4.30(2H,m),7.20-7.60(7H,m),7.70-7.80(2H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=12900).

EXAMPLE 27 ##STR67##

IR(KBr)cm⁻¹ : 3421,1745,1587,1386,1108,763,605.

¹ H-NMR(D₂ O)δ: 0.80(3H,d,J=7.4 Hz),0.89(3H,d,J=6.4 Hz),1.21-1.24(1H,m),2.26-2.31(1H,m),2.49(2H,d,J=7.3Hz),2.80-2.97(6H,m),3.04-3.07(1H,m),3.16-3.38(4H,m),3.40-3.58(5H,m),3.80-3.87(2H,m),7.06-7.14(4H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 298 nm (ε=9080).

EXAMPLE 28 ##STR68##

IR(KBr)cm⁻¹ : 2360,2333,1751,1741,1691,1675,1643,1593,1562, 1549,1514.

¹ H-NMR(D₂ O)δ: 1.07-1.21(6H,m),1.27-1.45(1H,m),2.72-2.82(1H,m),3.89-4.00(1H,m),4.09-4.12(1H,m),7.39-7.49(1H,m),7.52-7.77(1H,m),7.88-7.91(1H,m),8.44-8.46(1H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 296 nm (ε=26200).

EXAMPLE 29 ##STR69##

IR(KBr)cm⁻¹ : 1755,1633,1597,1550,1533,1394,1092.

¹ H-NMR(D₂ O)δ: 1.15(3H,d,J=7.3 Hz), 1.24(3H,d,J=6.3 Hz),1.77(1H,m),2.74(1H,m),3.23(2H,t,J=5.9Hz),3.30-3.45(4H,m),3.53-3.63(2H,m),3.68(2H,t,J=5.9Hz),3.83-4.04(2H,m),4.15-4.25(2H,m),7.53(2H,d,J=8.3 Hz), 7.75(2H,d,J=8.3 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=13700).

EXAMPLE 30 ##STR70##

IR(KBr)cm⁻¹ : 3429,2927,1747,1684,1653,1541,1398.

¹ H-NMR(D₂ O)δ: 1.13(3H,d,J=7.0 Hz), 1.23(3H,d,J=6.2 Hz),1.75(1H,m),2.70(1H,m),3.20-3.45(5H,m),3.55-3.75(5H,m),3.95(2H,m),4.19(2H,m),7.77(1H,d,J=7.9Hz), 7.98(1H,d,J=7.9 Hz),8.37(1H,s).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=18100).

EXAMPLE 31 ##STR71##

IR(KBr)cm⁻¹ : 1755,1641,1628,1595,1550,1460,1389,1302, 1250,1140.

¹ H-NMR(D₂ O)δ: 1.15(3H,d,J=7.3 Hz), 1.25(3H,d,J=6.3 Hz),1.82(1H,m),2.79(1H,m),3.25(2H,t,J=5.9Hz),3.30-3.45(3H,m),3.41(3H,s),3.55-3.75(3H,m),3.71(2H,t, J=5.9Hz),3.90-4.05(2H,m),7.73(1H,d,J=8.2 Hz), 8.05(1H,d,J=8.2 Hz),8.37(1H,s).

UVλ.sub._(max) (0.1M MOPS buffer, pH 7.0): 301 nm (ε=17300).

EXAMPLE 32 ##STR72##

IR(KBr)cm⁻¹ : 3429,2968,1753,1643,1595,1541,1456,1394,1317, 1153,1092.

¹ H-NMR(D₂ O)δ: 1.13(3H,d,J=7.2 Hz), 1.23(3H,d,J=6.4 Hz),1.79(1H,m),2.55(3H,s),2.76(1H,m),3.20-3.43(5H,m),3.60-3.84(5H,m),3.93-4.03(2H,m),4.13-4.22(2H,m),7.73(1H,d,J=8.4Hz),7.99(1H,dd, J=2.1&8.4 Hz),8.32(1H,d,J=2.1 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 298 nm (ε=15900).

EXAMPLE 33 ##STR73##

IR(KBr)cm⁻¹ : 3421,1747,1589,1408,1394,1282,1243.

¹ H-NMR(D₂ O)δ: 1.14(3H,d,J=7.1 Hz), 1.24(3H,d,J=6.4Hz),3.18-3.42(8H,m),3.55-3.62(1H,m),3.70-3.78(1H,m),3.88-3.95(2H,m),4.15-4.27(4H,m),7.01(2H,d,J=4.0Hz), 7.49(2H,d,J=8.7 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 297 nm (ε=7660).

EXAMPLE 34 ##STR74##

IR(KBr)cm⁻¹ : 2966,1749,1587,1394,1242.

¹ H-NMR(D₂ O)δ: 1.12(3H,d,J=7.4 Hz), 1.23(3H,d,J=6.4 Hz),1.67(1H,m),2.64(1H,m),3.20-3.40(5H,m),3.57(1H,m),3.78(1H,m),3.92(1H,m),4.12(2H,s),4.10-4.20(2H,m),7.04(2H,d,J=8.8Hz),7.06(2H,d,=8.4 Hz),7.41 (2H,d,J=8.4 Hz)7.51(2H,d,J=8.8Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300nm (ε=10000).

EXAMPLE 35 ##STR75##

IR(KBr)cm⁻¹ : 3446,1629,1392,1089,1051.

¹ H-NMR(D₂ O)δ: 0.80-1.00(2H,m), 1.17(3H,d,J=6.8 Hz), 1.27(3H,d,J=6.6Hz), 1.40-1.80(2H,m),1.80-2.00(3H,m),2.80-2.90(5H,m),3.60-3.80(4H,m),6.80(2H,d,J=8.5Hz),7.34(2H,d,J=7.2 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=3610).

EXAMPLE 36 ##STR76##

IR(KBr)cm⁻¹ : 1749,1668,1650,1589,1522,1471,1390,1308.

¹ H-NMR(D₂ O)δ: 1.12(3H,d,J=7.0 Hz), 1.23(3H,d,J=6.2 Hz),1.48(1H,m),2.10(3H,s),2.45(1H,m),2.90(1H,m),3.10-3.22(3H,m),3.22-3.40(3H,m),3.70(1H,m),4.08-4.24(2H,m),7.27(1H,dd,J=1.5&8.8Hz), 7.42(1H,d,J=8.5 Hz),7.58(1H,d,J=1.5 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=10900).

EXAMPLE 37 ##STR77##

IR (KBr) cm⁻¹ : 3423,2967,1751,1646,1589,1527,1396,1319.

¹ H-NMR(D₂ O)δ: 1.16 (3H,d,J=7.3 Hz),1.26 (3H,d,J=6.2 Hz),1.60-1.80(1H,m), 2.50-2.80 (1H,m), 3.20-3.70 (6H,m), 3.70-4.10 (2H,m), 4.10-4.30(3H,m), 4.60-5.40 (7H,m), 7.50-7.70 (6H,m),7.80-8.00 (2H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=19200).

EXAMPLE 38 ##STR78##

IR (KBr)cm⁻¹ : 3421,1747,1668,1591,1527,1494,1396,1344, 727,698.

¹ H-NMR(D₂ O)δ: 1.10 (3H,d, J=3.8 Hz), 1.26 (3E, d ,J=5.9 Hz), 2.20-2.50(1H,m), 2.70-3.00 (2H,m), 3.00-3.40 (6H,m),3.50-3.80(3H,m),4.00-4.30(3H,m),4.50-5.00(1H,m),7.10-7.50 (10H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=9610).

EXAMPLE 39 ##STR79##

IR(KBr)cm⁻¹ : 3432,1741,1646,1585,1396,1124,1089,601.

¹ H-NMR(D₂ O)δ: 1.16 (3H,d,J=7.1 Hz), 1.29 (4H,d,J=6.4 Hz), 2.70-3.80(11H,m), 4.10-4.40 (3H,m), 6.80-6.90 (2H,m), 7.20-7.40 (2H,m), 7.50-7.60(3H,m), 7.80-7.90 (2H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=6590).

EXAMPLE 40 ##STR80##

IR(KBr)cm⁻¹ : 3421,2967,1751,1683,1591,1538,1496,1398,1288.

¹ H-NMR(D₂ O)δ: 1.20(3H,d,J=7.4 Hz), 1.30(3H,d,J=6.3 Hz),1.70-1.90(1H,m),2.60-3.00(4H,m),3.20-3.50(9H,m),3.60-4.10(4H,m),4.20-4.30(3H,m),7.49(2H,d,J=8.5Hz), 7.55(2H,d,J=8.6 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=10800).

EXAMPLE 41 ##STR81##

IR(KBr)cm⁻¹ : 3417,2360,1751,1695,1592,1394.

¹ H-NMR(D₂ O)δ: 1.19(3H,d,J=7.4 Hz), 1.32(3H,d,J=6.3 Hz),1.70-1.80(1H,m),2.70-2.80(1H,m),3.30-4.10(9H,m),4.20-4.30(2H,m),4.60-5.00(4H,m),5.20(1H,s),7.30-7.70(10H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=11800).

EXAMPLE 42 ##STR82##

IR(KBr)cm⁻¹ : 3486,1731,1621,1151.

¹ H-NMR(D₂ O)δ: 1.12(3H,d,J=7.3 Hz), 1.26(3H,d,J=6.2 Hz),1.67-1.70(1H,m),2.15-2.20(1H,m),2.64-2.71 (1H,m),3.01(1H,t,J=7.2Hz),3.27-3.48(9H,m),3.50-3.64(3H,m),3.72-3.81(1H,m),3.91-4.00(2H,m),4.16-4.23 (2H,m),7.27(2H,d,J=9.3Hz),7.52(2H,d,J=9.2 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=9720).

EXAMPLE 43 ##STR83##

IR(KBr)cm⁻¹ : 1749,1558,1396,1089.

¹ H-NMR(D₂ O)δ: 1.18(3H,d,J=7.3 Hz), 1.28(3H,d,J=6.3 Hz),1.60-1.70(1H,m),2.60-2.70(1H,m),3.20-3.40(3H,m),3.40-3.50(3H,m),3.60-4.00(2H,m),4.16(2H,s),4.15-4.30 (2H,m), 7.43 (2H,d,J=8.6Hz), 7.54 (2H,d,J=8.6 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 297 nm (ε=8290).

EXAMPLE 44 ##STR84##

IR(KBr)cm⁻¹ : 3359,2964,1745,1583,1641,1388,1346,1103,765.

¹ H-NMR(D₂ O)δ: 0.81(3H,d,J=7.3 Hz),0.90(3H,d,J=6.3 Hz),1.15-1.19(1H,m),2.25-2.31(1H,m),2.47-2.49(2H,m),2.85-2.98(2H,m),3.05-3.08(1H,m),3.12-3.20(1H,m),3.22-3.40(1H,m),3.49(2H,s),3.50-3.59(1H,m),3.79-3.89(4H,m),7.07(4H,s).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 298 nm (ε=8840).

EXAMPLE 45 ##STR85##

IR(KBr)cm⁻¹ : 1749,1585,1390.

¹ H-NMR(D₂ O)δ: 1.15(3H,d,J=7.0 Hz), 1.25(3H,d,J=6.4 Hz),1.64-1.78(1H,m),2.61-2.73(1H,m),2.96(2H,t,J=7.3 Hz), 3.24 (2H,t,J=7.3Hz),3.20-3.50(5H,m), 3.58 (1H,dd,J=6.5&12.5Hz),3.71-3.86(1H,m),3.89-4.00 (1H,m),4.14-4.25(2H,m),7.30(2H,d,J=8.3Hz), 7.47 (2H,d,J=8.3 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 297 nm (ε=8820).

EXAMPLE 46 ##STR86##

IR(KBr)cm⁻¹ : 1755,1587,1390.

¹ H-NMR(D₂ O)δ: 1.16(3H,d,J=7.1 Hz), 1.26(3H,d,J=6.4 Hz),1.67-1.80(1H,m),2.62-2.78(1H,m),2.68(3H,s), 3.00(2H,t,J=7.4Hz),3.29(2H,t,J=7.0 Hz),3.22-3.50(5H,m),3.60(1H,dd,J=6.4&12.3Hz),3.75-3.89(1H,m),3.89-4.00(1H,m),4.14-4.26(2H,m),7.30(2H,d,J=8.0Hz),7.49(2H,d,J=8.0 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 297 nm (ε=9140).

EXAMPLE 47 ##STR87##

IR(KBr)cm⁻¹ : 1753,1593,1390.

¹ H-NMR(D₂ O)δ: 1.15(3H,d,J=7.4 Hz), 1.27(3H,d,J=6.4 Hz),1.75(1H,m),2.70(1H,m),3.20-3.80(7H,m),3.80-4.05(2H,m),4.25(1H,m),4.60(2H,s),4.70(4H,brs),7.30-7.68(8H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=8810).

EXAMPLE 48 ##STR88##

IR(KBr)cm⁻¹ : 3421,1751,1589,1392.

¹ H-NMR(D₂ O)δ: 1.18(3H,d,J=7.2 Hz), 1.27(3H,d,J=6.4 Hz),1.73(1H,m),2.72(1H,m),3.25-4.30(6H,m),4.11(4H,s),4.48(2H,s),5.92(2H,s),7.50(2H,d,J=8.4 Hz), 7.58 (2H,d,J=8.4 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=9360).

EXAMPLE 49 ##STR89##

IR(KBr)cm⁻¹ : 1755,1581,1387,1296.

¹ H-NMR(D₂ O)δ: 1.05(3H,d,J=7.0 Hz), 1.26(3H,d,J=6.4 Hz), 1.56-1.69(1H,m),2.55-2.68(1H,m),3.20-3.50(5H,m),3.56-3.67(1H,m),3.77-3.96(2H,m),4.11-4.30(2H,m), 4.25(2H,s),4.5-5.0,7.40(2H,d,J=8.3 Hz),7.50-7.60 (4H,m),7.82(2H,d,J=6.6 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=8950).

EXAMPLE 50 ##STR90##

IR(KBr)cm⁻¹ : 3423,2967,1751,1679,1587,1454,1396.

¹ H-NMR(D₂ O)δ: 1.22(3H,d,J=6.7 Hz), 1.32(3H,d,J=6.3 Hz),1.70-1.80(1H,m),2.68-2.77(1H,m),3.30-3.55(2H,m),3.60-4.11(4H,m),4.20-4.30(3H,m),7.37(2H,d,J=9.3Hz), 7.54(2H,d,J=9.3 Hz).

EXAMPLE 51 ##STR91##

IR(KBr)cm⁻¹ : 1753,1664,1595,1390,1288,1149.

¹ H-NMR(D₂ O)δ: 1.11(3H,d,J=7.1 Hz), 1.25(3H,d,J=6.1 Hz),1.56-1.70(1H,m),2.54-2.70(1H,m),3.20-4.80(12H,m),4.42(3H,s),7.24-7.51(5H,m),8.40(2H,d,J=6.4 Hz), 8.90(2H,d,J=6.4 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=10600).

EXAMPLE 52 ##STR92##

IR(KBr)cm⁻¹ : 1749,1589,1387.

¹ H-NMR(D₂ O)δ: 1.11(3H,d,J=7.1 Hz), 1.21(3H,d,J=6.4 Hz), 1.59-1.60(1H,m),2.56-2.70(1H,m),3.20-3.32(3H,m),3.35-3.56(3H,m),3.68-3.80(1H,m),3.81(3H,s),3.84-3.93(1H,m),4.11-4.21(2H,m),5.31(2H, s), 7.33 (2H,d,J=8.6Hz),7.36-7.43(2H,m), 7.48 (2H,d,J=8.6 Hz),8.69(1H,s).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=9520).

EXAMPLE 53 ##STR93##

IR(KBr)cm⁻¹ : 1749,1668,1576,1394.

¹ H-NMR(D₂ O)δ: 1.16(3H,d,J=7.1 Hz), 1.26(3H,d,J=6.1 Hz),1.67-1.81(1H,m),2.64-2.80(1H,m),3.26-3.50(4H,m),3.50-3.62(2H,m),3.78-3.91(1H,m),3.92-4.02(1H,m),4.17-4.23(2H,m),4.23(2H,s),7.74(2H,s),7.91(1H,s).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 298 nm (ε=10000).

EXAMPLE 54 ##STR94##

IR(KBr)cm⁻¹ : 1753,1599,1390.

¹ H-NMR(D₂ O)δ: 1.20(3H,d,J=7.0 Hz), 1.28(3H,d,J=6.0 Hz),1.75(1H,m),2.73(1H,m),7.40-7.65(3H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=6130).

EXAMPLE 55 ##STR95##

IR(KBr)cm⁻¹ : 3421,1749,1670,1589,1394,1288,1107,813.

¹ H-NMR(D₂ O)δ: 1.18(3H,d,J=7.3 Hz), 1.28(3H,d,J=6.4 Hz),1.38(1H,m),2.47(1H,m),2.92(1H,dd,J=3.7&12.3Hz),3.10-4.30(6H,m),3.67(2H,s),3.72(1H,m),4.20(2H,m), 7.41(4H,s).

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm (ε=10300).

EXAMPLE 56 ##STR96##

IR(KBr)cm⁻¹ : 3386,1751,1591,1394,1288,1106,813.

¹ H-NMR(D₂ O)δ: 1.18(3H,d,J=6.9 Hz), 1.29(3H,d,J=6.4 Hz),1.39(1H,m),2.43(1H,m),2.93(1H,dd,J=3.6&12.0 Hz), 3.13(2H,t,J=6.2Hz),3.10-3.40(6H,m),3.70(1H,m), 3.74(2H,t,J=6.2Hz),4.10-4.30(2H,m),7.41(4H,s)

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=11100).

EXAMPLE 57 ##STR97##

IR(KBr)cm⁻¹ : 1747,1718,1649,1633,1591,1560,1543,1394,1153.

¹ H-NMR(D₂ O)δ: 1.16(3H,d,J=7.0 Hz), 1.25(3H,d,J=6.4 Hz),1.78(1H,m),2.75(1H,m),3.25-3.50(4H,m),3.56-3.70(2H,m),3.85-4.04(2H,m),4.15-4.26(2H,m),4.48(2H,s),7.61(1H,d,J=7.9 Hz),7.76(1H,d,J=7.9 Hz), 8.05 (1H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=10800).

EXAMPLE 58 ##STR98##

IR(KBr)cm⁻¹ : 3409,2967,1754,1579,1394,1309,1280,1151,1095, 1078,763.

¹ H-NMR(D₂ O)δ: 1.19(3H,d,J=7.3 Hz), 1.27(3H,d,J=6.4 Hz),1.81(1H,m),2.79(1H,m),3.30-3.80(10H,m),3.95(2H,m),4.23(2H,m),7.67(2H,d,J=8.4 Hz),7.92(2H,d,J=8.4 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=13910).

EXAMPLE 59 ##STR99##

IR(KBr)cm⁻¹ : 3425,2968,2364,1753,1672,1605,1392,1284,1101.

¹ H-NMR(D₂ O)δ: 1.19(3H,d,J=7.3 Hz), 1.29(3H,d,J=6.3 Hz),1.70-1.80(1H,m),2.71-2.80(1H,m),3.20-3.70(8H,m),3.90-4.10(3H,m),4.20-4.30(2H,m),7.50-7.60(4H,m).

UVλmax (0.1M MOPS buffer, pH 7.0): 300 nm (ε=10800).

EXAMPLE 60 ##STR100##

IR(KBr)cm⁻¹ : 3421,2970,1749,1633,1597,1487,1394,1290, 1255,1097.

¹ H-NMR(D₂ O)δ: 1.19(3H,d,J=7.0 Hz), 1.29(3H,d,J=6.5 Hz),1.70-1.80(1H,m),2.70-2.80(1H,m),3.30-3.70(8H,m),3.80-3.90(2H,m),3.95-4.05(1H,m),4.20-4.30(2H,m),7.50(4H,m)UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=10100).

EXAMPLE 61 ##STR101##

IR(KBr)cm⁻¹ : 3421,2966,1753,1587,1390,1255,1145,1085,765.

¹ H-NMR(D₂ O)δ: 1.13(3H,d,J=5.8 Hz), 1.23(3H,d,J=4.8 Hz),1.67(1H,m),2.67-2.70(3H,m),3.11-3.89(12H,m),4.10-4.20(2H,m),7.33(2H,d),7.44(2H,d).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 296 nm (ε=7330).

EXAMPLE 62 ##STR102##

IR(KBr)cm⁻¹ : 1753,1577,1392.

¹ H-NMR(D₂ O)δ: 1.08(3H,d,J=9.3 Hz), 1.12(3H,d,J=6.0 Hz),1.20-1.65(2H,m),3.80-4.10(2H,m),4.90-5.05(1H,br),6.92(1H,d,J=8.1Hz),7.09-7.17(1H,m),7.40-7.57(4H,m),7.60-7.70(1H,m),8.36-8.40(1H,m).

UVλmax (0.1M MOPS buffer, pH 7.0): 300 nm (ε=18300).

EXAMPLE 63 ##STR103##

IR(KBr)cm⁻¹ : 3421,2970,1745,1583,1390,1336,1157,1099.

¹ H-NMR(D₂ O)δ: 1.14(3H,d,J=7.2 Hz), 1.23(3H,d,J=6.3Hz),3.05-3.15(4H,m),3.30-3.45(4H,m),3.50-3.65(2H,m),3.80-4.00(2H,m),4.10-4.25(2H,m),7.60(2H,d,J=8.7Hz), 7.80(2H,d,J=8.7 Hz).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=11700).

EXAMPLE 64 ##STR104##

IR(KBr)cm⁻¹ : 3375,2966,1751,1662,1600,1577,1394,1284,1261.

¹ H-NMR(D₂ O)δ: 1.14(3H,d,J=7.2 Hz), 1.24(3H,d,J=6.4 Hz),1.63-1.73(1H,m),2.62-2.70(1H,m),3.15-3.19(2H,m),3.26-3.36(5H,m),3.40-3.47(2H,m),3.58(1H,m),3.78(1H,m),3.93(1H,m),4.15-4.22(2H,m),7.53-7.59(3H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=12700).

In the following Example 65 to 68, compounds represented by the formula(B) which have substituents R₃ and R₄ were synthesized in the samemanner as in Examples 1 to5. ##STR105##

EXAMPLE 65 ##STR106##

IR(KBr)cm⁻¹ : 3420,2970,1750,1590,1390,1290,1150,740.

¹ H-NMR(D₂ O)δ: 1.12(3H,d,J=7.0 Hz), 1.22(3H,d,J=6.0Hz),2.00-2.20(2H,m),3.00-3.20(2H,m),3.20-3.30(2H,m),3.40(1H,m),3.55(1H,m),3.75(1H,m),3.90(1H,m), 4.20(2H,m),7.20-7.50(5H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 297 nm (ε=9970).

EXAMPLE 66 ##STR107##

IR(KBr)cm⁻¹ : 3420,2970,1750,1590,1400.

¹ H-NMR(D₂ O)δ: 1.11(3H,d,J=7.0 Hz), 1.26(3H,d,J=6.0 Hz),1.80-2.00(2H,m),2.50(1H,m),2.70(1H,m),3.05(1H,m),3.15-3.50(4H,m),3.60-3.80(2H,m),4.00-4.25(2H,m),7.20-7.50(5H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 299 nm (ε=7450).

EXAMPLE 67 ##STR108##

IR(KBr)cm⁻¹ : 3420,2970,1750,1590,1390,1280,1180,1150, 1070,740.

¹ H-NMR(D₂ O)δ: 1.09(3H,d,J=7.0 Hz), 1.23(3H,d,J=6.0 Hz),1.70(1H,m),2.50(1H,m),3.10-3.50(6H,m),3.60(1H,m),3.80(1H,m),4.05(1H,m),4.20(1H,m),7.20-7.50(5H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 298 nm (ε=9150).

EXAMPLE 68 ##STR109##

IR(KBr)cm⁻¹ : 3390,1753,1587,1390.

¹ H-NMR(D₂ O)δ: 1.10(3H,d,J=6.0 Hz), 1.15(3H,d,J=6.0 Hz),1.45(1H,m),2.45(1H,m),2.70-3.30(6H,m),3.60(1H,m),3.70(1H,m),4.00(2H,m),7.30(5H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 298 nm (ε=7780).

In the following Examples 69 to 123, compounds represented by theformula (A) which have substituents R₁ and R₂ were synthesized in thesame manner as in Examples to 5. ##STR110##

EXAMPLE 69 ##STR111## Diastereomer A

IR(KBr)cm⁻¹ : 1755,1597,1394.

¹ -NMR(D₂ O)δ: 1.13(3H,d,J=7.0 Hz), 1.26(3H,d,J=6.0 Hz),3.22(1H,m),3.36(1H,m),4.43(1H,m),7.41(3H,m), 7.62(2H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=7040).

Diastereomer B

IR(KBr)cm⁻¹ : 1755,1597,1394.

¹ H-NMR(D₂ O)δ: 1.05(3H,d,J=7.0 Hz), 1.27(3H,d,J=6.0 Hz),4.40(1H,m),7.43(3H,m),7.62(2H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 297 nm (ε=6530).

EXAMPLE 70 ##STR112## Diastereomer A

IR(KBr)cm⁻¹ : 3047,1754,1594,1390.

¹ -NMR(D₂ O)δ:1.10-1.30(6H,m),2.80-4.30(m),7.40-7.55(3H,m),7.70-7.85(4H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=8100).

Diastereomer B

IR(KBr)cm⁻¹ : 3444,1756,1594,1392.

¹ H-NMR(D₂ O)δ:1.10-1.40(6H,m),2.80-4.30(m),7.40-7.55(3H,m),7.70-7.90(4H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=9220).

EXAMPLE 71 ##STR113##

IR(KBr)cm⁻¹ : 1759,1600,1390.

¹ H-NMR(D₂ O)δ: 1.21(3H,d,J=7.0 Hz), 1.31(3H,d,J=6.0 Hz),1.77(1H,m),2.74(1H,m),3.65(1H,dd,J=3.0&8.0 Hz),3.89(1H,m),4.00(1H,m),4.20-4.30(2H,m), 7.44(1H,d,J=8.0 Hz),7.55(2H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=10400).

EXAMPLE 72 ##STR114## Diastereomer A

IR(KBr)cm⁻¹ : 3425,2930,1750,1580,1460,1390,1280.

¹ H-NMR(D₂ O)δ: 1.21(3H,d,J=7.4 Hz), 1.30(3H,d,J=6.3 Hz),1.60-2.10(3H,m),2.50-2.70(1H,m),3.10-3.80(9H,m),3.80-4.00(1H,m),4.10-4.30(2H,m),4.80(2H,s),7.40-7.50(3H,m),7.50-7.60(3H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 299 nm (ε=9100).

Diastereomer B

IR(KBr)cm⁻¹ : 3420,2970,1755,1580,1390.

¹ H-NMR(D₂ O)δ: 1.22(3H,d,J=6.7 Hz), 1.30(3H,d,J=6.3 Hz),1.80-2.10(2H,m),2.70-2.90(1H,m),3.10-3.60(8H,m),3.70-3.80(1H,m),3.90-4.10(1H,br),4.20-4.30(2H,m),4.80(3H,s),7.40-7.50(3H,m),7.50-7.60(3H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 299 nm (ε=8690).

EXAMPLE 73 ##STR115##

IR(KBr)cm¹ : 1751,1583.

¹ H-NMR(D₂ O)δ: 1.29(3H,d), 1.31(3H,d),2.19(1H,m),2.80(2H,m),3.30(5H,m),3.74(1H,m),4.23(2H,m),7.60(8H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=11200).

EXAMPLE 74 ##STR116##

IR(KBr)cm⁻¹ : 1745,1585.

¹ H-NMR(D₂ O)δ: 1.13(3H,d), 1.28(3H,d), 1.38(1H,m),2.20(1H,m),2.34(1H,m),2.59(2H,m),2.98(1H,m),3.45(4H,m),3.83(1H,m),4.22(2H,m),7.34(2H,m),7.56(6H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=8000).

EXAMPLE 75 ##STR117##

IR(KBr)cm⁻¹ : 1753,1677,1581.

¹ H-NMR(D₂ O)δ: 1.80(3H,d), 1.31(3H,d), 1.66(1H,m),2.63(1H,m),3.29(4H,m),3.46(1H,m),3.67(3H,m),3.79(1H,m),3.92(1H,m),4.21(4H,m),7.31(2H,m),7.52(6H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=8010).

EXAMPLE 76 ##STR118##

IR(KBr)cm⁻¹ : 3421,2966,1750,1580,1392.

¹ H-NMR(D₂ O)δ: 1.02(3H,d,J=6.8 Hz), 1.10(3H,d,J=6.3 Hz),1.50-1.60(1H,m),2.25-2.41(3H,m),2.55-2.90(3H,m),3.08-3.48(5H,m),3.51-3.95(2H,m),4.95-5.04(1H,m),7.39-7.70(8H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=9810).

EXAMPLE 77 ##STR119## EXAMPLE 78 ##STR120## IR(KBr)cm⁻¹ :3435,1755,1699,1587,1390,1259,1171,1030.

¹ H-NMR(D₂ O)δ: 1.10(3H,d,J=7.3 Hz),1.22(3H,d,J=6.5 Hz),1.65-1.71(1H,m),2.10-2.16(1H,m),2.64-2.70(1H,m),2.92-2.98(1H,m),3.18-3.61(8H,m),3.86-4.38(16H,m),4.84(2H,br s),7.45-7.68(7H,m),7.95(1H,br s).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=8020). EXAMPLE 79##STR121##

IR(KRr)cm⁻¹ : 3405,2968,1749,1593,1541,1388.

¹ H-NMR(D₂ O)δ: 1.10(3H,d),1.20(3H,d),1.75(1H,m),2.70(1H,m),3.20-4.30(12,m),7.40-8.10(7H,m).

UV_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=7480).

EXAMPLE 80 ##STR122##

IR(KBr)cm⁻¹ : 3419,1749,1594,1394.

¹ H-NMR(D₂ O)δ: 1.10(6H,m),7.48(2H,m),7.54(2H,m),7.62(2H,m), 7.72(2H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=18400).

EXAMPLE 81 ##STR123##

IR(KBr)cm⁻¹ : 1753,1581.

¹ H-NMR(D₂ O)δ: 1.81(3H,d), 1.29(3H,d), 1.78(1H,m), 1.90(1H,m),2.52(3H,s),2.76(1H,m),3.42(3H,m),3.63(2H,m),3.76(2H,m),3.98(2H,m),4.26(3H,m),7.59(8H,m).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 300 nm (ε=11100).

EXAMPLE 82 ##STR124##

IR(KBr)cm⁻¹ : 3433,2968,1753,1659,1605,1390.

¹ H-NMR(D₂ O)δ: 1.09(3H,d,J=7.0 Hz), 1.22(3H,d,J=6.3 Hz),1.71(1H,m),2.67(1H,m),3.15(2H,t),3.20-3.40(6H,m),3.48(1H,m),3.56(1H,m),3.84(1H,m),3.92(1H,m), 4.15(2H,m),7.54(2H,d,J=8.0Hz),7.63(2H,d,J=8.0 Hz), 7.75(2H,d).

UVλ_(max) (0.1M MOPS buffer, pH 7.0): 297 nm (ε=33500).

EXAMPLE 83 ##STR125##

IR(KBr)cm⁻¹ : 3417,3386,2966,1753,1577,1452,1388,1263.

¹ H-NMR(D₂ O)δ: 1.07(3H,d,J=7.2 Hz), 1.21(3H,d,J=6.4 Hz),1.57-1.75(1H,m),2.50-2.70(1H,m),3.13-3.66(6H,m),3.76-3.97(2H,m),4.02-4.23(2H,m),4.63(2H,s),7.52-7.55(1H,m),7.68-7.74(3 H,m),8.04-8.09(1 H,m),8.43-8.48(1 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 302 nm(ε=16800)

Example 84 ##STR126##

IR(KBr)cm⁻¹ : 3430,2970,1750,1580,1450,1390,1280,1150,890

¹ H-NMR(D₂ O)δ: 1.09(3 H,d,J=7.0 Hz),1.23(3 H,d,J=6.0 Hz), 1.70(1H,m),2.60(1 H,m),3.20-3.45(3 H,m),3.45-3.65(3 H,m),3.85-4.00(2H,m),4.10-4.30(2 H,m), 4.35(2 H,s),4.41(2 H,s),7.66(1 H,d,J=8.0 Hz),7.84(1 H,s),7.97(1 H,s),8.06(1 H,d,J=9.0 Hz),8.47(1 H,s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=14000)

Example 85 ##STR127##

IR(KBr)cm⁻¹ : 3430,1754,1672,1592,1388

¹ H-NMR(D₂ O)δ: 1.09-1.11(3 H,m),1.23-1.25(3 H,m),1.64-1.69(1H,m),2.53-2.60(1 H,m),3.22-3.56(6 H,m),3.67-3.73(1 H,m),3.83-3.88(1H,m),4.13-4.21(2 H,m),5.80-5.81(1 H,m),7.54-7.67(3 H,m),7.81(1 H,d,J=7.0Hz), 8.19(1 H,d,J=8.8 Hz),8.49-8.52(1 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 301 nm(ε=17900)

Example 86 ##STR128##

IR(KBr)cm⁻¹ : 3390,2970,1750,1590,1390,1090

¹ H-NMR(D₂ O)δ: 1.08(3 H,d,J=7.4 Hz),1.22(3 H,d,J=6.5 Hz),1.70-1.82(1H,m),2.65-2.75(1 H,m),3.20-3.45(4 H,m),3.55-3.65(2 H,m),3.80-4.00(2H,m),4.10-4.20(2 H,m), 4.31(2 H,s),7.50-7.60(2 H,m),7.85-7.95(3H,m),7.99(1 H,s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=14700)

Example 87 ##STR129## Diastereomer A

IR(KBr)cm⁻¹ : 3425,1747,1670,1585,1395

¹ H-NMR(D₂ O)δ: 1.01(3 H,d,J=6.1 Hz),1.25(3 H,d,J=6.5 Hz),1.40-1.60(1H,m),2.10-2.80(3 H,m),2.90-3.90(7 H,m),4.00-4.30(2 H,m),7.30-7.60(3H,m),7.70-8.10(4 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=11600)

Diastereomer B

IR(KBr)cm⁻¹ : 3425,1747,1670,1590,1395

¹ -NMR(D₂ O)δ: 0.88(3 H,d,J=6.8 Hz),1.23(3 H,d,J=6.1 Hz),1.30-1.50(1H,m),2.20-2.70(3 H,m),2.70-3.60(6 H,m),3.60-3.80(1 H,m),4.00-4.30(2H,m),7.20-7.70(6 H,m),7.80-7.90(1 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=11800)

Example 88 ##STR130##

IR(KBr)cm⁻¹ : 3415,2967,1750,1580,1450,1390,1285,1267,775

¹ H-NMR(D₂ O)δ: 1.14(3 H,d,J=7.1 Hz),1.27(3 H,d,J=6.4 Hz),2.30-2.40(2H,m),2.80-2.90(2 H,m),3.10-3.60(6 H,m),3.70-3.80(2 H,m),4.10-4.40(4H,m),7.50-7.70(4 H,m),8.00-8.10(2 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=14200)

Example 89 ##STR131##

IR(KBr)cm⁻¹ : 3421,2969,1749,1585,1392,1317,1149

¹ H-NMR(D₂ O)δ: 1.03(3 H,d,J=7.1 Hz),1.20(3 H,d,J=6.2 Hz),2.20-2.30(2H,m),2.70-2.90(2 H,m),3.10-3.50(6 H,m),3.70 3.80(1 H,m),4.00-4.20(2H,m),4.30-4.40(2 H,m),7.60(1 H,d,J=8.0 Hz),7.70-7.80(2 H,m),8.20(1H,d,J=7.8 Hz),8.70(1 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=17710)

Example 90 ##STR132##

IR(KBr)cm⁻¹ : 3428,2969,2362,1753,1606,1392

¹ H-NMR(D₂ O)δ: 1.12(3 H,d,J=7.2 Hz),1.27(3 H,d,J=6.2 Hz),1.40-1.50(1H,m),2.50-2.60(1 H,m),2.80-3.00(2 H,m),3.20-3.30(2 H,m),3.40-3.50(1H,m),3.50-3.60(1 H,m),3.70-3.80(1 H,m),3.80-3.90(1 H,m),4.01(2H,s),4.10-4.30(2 H,m),4.35(2 H,s),4.20-4.80(5 H,m),7.50-7.70(2H,m),7.80-8.00(4 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=9040)

Example 91 ##STR133##

6Diastereomer A

IR(KBr)cm⁻¹ : 3390,2930,1755,1590,1385,1260

¹ H-NMR(D₂ O)δ: 1.17(3 H,d,J=7.4 Hz),1.28(3 H,d,J=6.3 Hz),1.60-2.00(3H,m),2.60-4.30(15 H,m),4.80(1 H,s),7.30-7.60(5 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 298 nm(ε=10140)

Diastereomer B

IR(KBr)cm⁻¹ : 3400,2965,1750,1590,1390,1075,750,610

¹ H-NMR(D₂ O)δ: 1.18(3 H,d,J=7.5 Hz),1.28(3 H,d,J=6.3 Hz),1.40-1.50(1H,m),2.40-2.60(1 H,m),2.90-3.00(1 H,m),3.20-3.50(6 H,m),3.70-3.90(3H,m),4.10-4.30(2 H,m),4.60-4.90(3 H,m),7.30-7.50(3 H,m),7.50-7.60(2 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 298 nm(ε=9070)

Example 92 ##STR134## Diastereomer A

IR(KBr)cm⁻¹ : 3340,2950,1750,1585,1385,1280,1140,1065,775

¹ H-NMR(D₂ O)δ: 0.98(3 H,d,J=6.6 Hz),1.30(3 H,d,J=6.3 Hz),1.60-1.80(2H,m),1.90-2.10(1 H,m),2.10-2.20(1 H,m),2.50-2.70(1 H,m),3.00-3.50(4H,m),3.50-3.70(2 H,m),3.70-3.90(1 H,m),4.10-4.30(1 H,m),7.40-8.00(6H,m),8.30-8.40(1 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=14700)

Diastereomer B

IR(KBr)cm⁻¹ : 3410,2965,1755,1585,1390,1280,1145,1085,775

¹ H-NMR(D₂ O)δ: 1.17(3 H,d,J=7.0 Hz),1.29(3 H,d,J=6.3 Hz),1.70-2.20(3H,m),2.70-2.80(1 H,m),3.20-3.50(5 H,m),3.60-3.70(2 H,m),3.90-4.10(1H,m),4.20-4.30(2 H,m),7.50-7.80(3 H,m),7.90(1 H,m),8.00-8.10(2H,m),8.50-8.60(1 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 299 nm(ε=14200)

Example 93 ##STR135##

IR(KBr)cm⁻¹ : 3430,2970,1750,1590,1400,1070

¹ H-NMR(D₂ O)δ: 0.99(3 H,d,J=6.0 Hz),1.20(3 H,d,J=6.0 Hz), 2.25(1H,m),2.70-3.60(9 H,m),4.00-4.20(2 H,m),7.20-7.90(7 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=10860)

Example 94 ##STR136##

IR(KBr)cm⁻¹ : 3425,2967,1753,1596,1390,1079,754,703,605

¹ H-NMR(D₂ O)δ: 1.03(1 H,m),1.20(3 H,d,J=7.4 Hz), 1.25(3 H,d,J=6.0Hz),3.65(2 H,m),4.13(1 H,m),7.18-7.49(10 H,m)

UVλmax(0.1M MOPS buffer, pH7.0): 300 nm(ε=8780)

Example 95 ##STR137##

IR(KBr)cm⁻¹ : 3419,1749,1595,1394

¹ H-NMR(D₂ O)δ: 1.10(3 H,br d),1.25(3 H,br d),1.75(1 H,m), 2.70(1H,m),3.40(6 H,m),3.60(1 H,m),3.85(3 H,br s),3.90(1 H,m),4.20(2H,m),5.42(2 H,br s),7.40-7.80(10 H,m),8.80(1 H,br s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=19500)

Example 96 ##STR138##

IR(KBr)cm⁻¹ : 1743,1585

¹ H-NMR(D₂ O)δ: 1.25(6 H,m),1.79(1 H,m),2.83(1 H,m),2.85(6 H,s), 3.40(3H,s),3.80(12 H,m),7.53(8 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=10300)

Example 97 ##STR139##

IR(KBr)cm⁻¹ : 1743,1585

¹ H-NMR(DMSO-d₆)δ: 0.89(1 H,m),1.05(3 H,d,J=6.9 Hz), 1.13(3 H,d,J=6.3Hz),1.92(1 H,m),2.31(1 H,m), 2.48(1 H,m),2.78(1 H,m),3.37(5 H,m),3.84(3H,s), 3.89(1 H,m),4.06(1 H,m),7.43(6H,m),7.49(2 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=10600)

Example 98 ##STR140##

IR(KBr)cm⁻¹ : 3421,2964,1747,1591,1386,1103,763,605

¹ H-NMR(D₂ O)δ: 0.78(3 H,d,J=7.0 Hz),0.87(3 H,d,J=6.3 Hz),1.27-1.30(1H,m),2.26-2.31(1 H,m),2.31-2.53(2 H,m),2.90-2.95(2 H,m),3.03-3.06(1H,m),3.18-3.34(2 H,m),3.48(2 H,s),3.52-3.57(1 H,m),3.78-3.85(2H,m),7.03-7.45(4 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 297 nm(ε=8880)

Example 99 ##STR141##

IR(KBr)cm⁻¹ : 1751,1587,1384

¹ H-NMR(D₂ O)δ: 1.16(3 H,d,J=7.4 Hz),1.26(3 H,d,J=6.3 Hz),1.68-1.80(1H,m),2.63-2.78(1 H,m),2.90(6 H,s), 3.06(2 H,t,J=7.4 Hz),3.25-3.52(7H,m), 3.61(1 H,dd,J=6.6 & 12.5 Hz),3.77-3.89(1 H,m), 3.90-4.00(1H,m),4.16-4.27(2 H,m),7.32(2 H,d,J=8.0 Hz), 7.49(2 H,d,J=8.0 Hz)

UVλ_(max) (0-1M MOPS buffer, pH7.0): 297 nm(ε=9580)

Example 100 ##STR142##

IR(KBr)cm⁻¹ : 3421,1741,1585,1461,1390,1340

¹ H-NMR(D₂ O)δ: 1.01(3 H,d),1.24(3 H,d,J=6.1 Hz),2.70-3.40(7H,m),4.00-4.30(2 H,m),7.00-7.60(6 H,m), 7.86(2 H,d,J=8.1 Hz)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=8610)

Example 101 ##STR143##

IR(KBr)cm⁻¹ : 1768,1749,1649,1616,1595,1579,1562,1540,1105

¹ H-NMR(D₂ O)δ: 1.18(3 H,d,J=7.1 Hz),1.27(3 H,d,J=6.4 Hz), 1.77(1H,m),2.74(1 H,m),3.07(3 H,s),3.29-3.47(4 H,m),3.52-3.66(2 H,m),3.83(1H,m),3.96(1 H,m), 4.17-4.27(2 H,m),4.53(2 H,s),7.57(1 H,d,J=8.0 Hz),7.72(1 H,dd,J=1.9 & 8.0 Hz),8.02(1 H,d,J=1.9 Hz)

UVλ_(max) (0.1M MOPS buffer, pH7.0 ): 300 nm(ε=10400)

Example 102 ##STR144##

IR(KBr)cm⁻¹ : 3423,2966,1755,1603,1458,1390,1327,1155

¹ H-NMR(D₂ O)δ: 1.13(3 H,d,J=6.9 Hz),1.23(3 H,d,J=6.4 Hz), 1.68(1H,m),2.63(1 H,m),2.70(2 H,t,J=6.7 Hz), 3.12(2 H,t,J=6.7 Hz),3.25-3.70(6H,m),3.84(2 H,s),3.91(2 H,m),4.19(2 H,m), 7.62(1 H,d,J=8.0 Hz),7.70(1H,d,J=8.0 Hz),8.00(1 H,s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 298 nm(ε=13100)

Example 103 ##STR145##

IR(KBr)cm⁻¹ : 3419,2964,2925,1749,1733,1600,1540,1519, 1506,1488

¹ H-NMR(D₂ O)δ: 1.07(3 H,d,J=7.1 Hz),1.18(3 H,d,J=6.3 Hz), 7.42-7.72(m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=8000)

Example 104 ##STR146##

IR(KBr)cm⁻¹ : 3388,1741,1646,1587,1396,1072,765,607

¹ H-NMR(D₂ O)δ: 1.17(3 H,d,J=6.6 Hz),1.28(3 H,d,J=6.3 Hz),2.30-2.60(3H,m),3.10-3.50(6 H,m),4.10-4.30(3 H,m),7.30-7.40(7 H,m),7.88(2 H,d,J=7.7Hz)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=14200)

Example 165 ##STR147## Diastereomer A

IR(KBr)cm⁻¹ : 3442,1750,1590,1400,1065

¹ H-NMR(D₂ O)δ: 0.80-1.30(m),1.50-4.30(m),7.00-7.60(m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=5000)

Diastereomer B

IR(KBr)cm⁻¹ : 3410,1740,1665,1621,1400

¹ H-NMR(D₂ O)8: 0.90-1.30(m),1.60-4.30(m),6.90-7.50(m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=3080)

Example 106 ##STR148##

IR(KBr)cm⁻¹ : 1756,1594,1257,1099

¹ H-NMR(D₂ O)δ: 1.18(3 H,d,J=6.3 Hz),1.28(3 H,d,J=6.4 Hz), 1.60(1H,m),2.55-2.90(3 H,m),3.20-3.45(2 H,m),3.50-4.00(12 H,m),4.15-4.30(2H,m),6.70-6.80(2 H,m), 7.30(1 H,m)

UV.sub.λmax (0.1M MOPS buffer, pH7.0): 298 nm(ε=7930)

Example 107 ##STR149## Diastereomer A

IR(KBr)cm⁻¹ : 3415,1750,1640,1590,1395,1290

¹ H-NMR(D₂ O)δ: 1.08(3 H,d,J=7.0 Hz),1.27(3 H,d,J=6.2 Hz),1.40-1.70(2H,m),1.81(3 H,s),2.20-2.40(1 H,m),2.80-3.00(1 H,m),3.10-3.70(9H,m),4.10-4.30(2 H,m),7.40-7.60(3 H,m),7.80-7.90(3 H,m),7.90(1 H,s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=11100)

Diastereomer B

¹ H-NMR(D₂ O)δ: 1.00-4.50(m),7.40-7.60(m),7.70-8.00(m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=7370)

Example 108 ##STR150##

IR(KBr)cm⁻¹ : 1753,1579,1390

¹ H-NMR(D₂ O)δ: 1.09(3 H,d,J=7.0 Hz),1.19(3 H,d,J=6.4 Hz),1.50-1.67(5H,m),2.51-2.65(3 H,m),2.82-2.95(2 H,m),3.15-3.38(3 H,m),3.44-3.53(1H,m),3.62-3.76(1H,m),3.80-3.90(1 H,m),4.09-4.18(2 H,m),7.20(2 H,d,J=7.8Hz), 7.37(2 H,d,J=7.8 Hz)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 297 nm(ε=3470)

Example 109 ##STR151## Diastereomer A

IR(KBr)cm⁻¹ : 3420,2970,1750,1590,1395,1310,1150

¹ H-NMR(D₂ O)δ: 0.96(3 H,d,J=5.0 Hz),1.24(3 H,d,J=6.1 Hz),1.30-2.10(4H,m),2.92(3 H,s),3.00-3.50(9 H,m),4.00-4.20(2 H,m),7.00-8.00(7 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=11300)

Diastereomer B

IR(KBr)cm⁻¹ : 3490,1745,1641,1590,1390,1310,1150

¹ H-NMR(D₂ O)δ: 0.93(3 H,d,J=6.3 Hz),1.24(3 H,d,J=6.3 Hz),1.10-2.30(4H,m),2.92(3 H,s),2.90-3.10(4 H,m),3.20-3.50(5 H,m),4.00-4.30(2H,m),7.20-7.90(7 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=8940)

Example 110 ##STR152##

IR(KBr)cm⁻¹ : 3421,1741,1645,1587,1566,1516,761,607

¹ H-NMR(D₂ O)δ: 1.13(3 H,d,J=7.0 Hz),1.22(3 H,d,J=6.4 Hz),1.50-1.65(1H,m),2.00-2.12(1 H,m),2.52-2.70(1 H,m),2.80-3.15(2 H,m),3.21-3.44(2H,m),3.50-3.96(3 H,m),4.12-4.22(1 H,m),5.45(1 H,s),7.26-7.60(6H,m),7.75-7.85(1 H,m),8.40-8.48(1 H,m),9.88(1 H,s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 298 nm(ε=8190)

Example 111 ##STR153##

IR(KBr)cm⁻¹ : 3421,1749,1589,1509

¹ H-NMR(D₂ O)δ: 1.20(3 H,d,J=7.0 Hz),1.28(3 H,d,J=6.4 Hz), 1.65(1H,m),2.65-3.10(3 H,m),3.25-3.65(4 H,m), 4.05(3 H,s),3.75-4.30(6H,m),7.76(1 H,d,J=1.2 Hz), 7.84(1 H,s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 297 nm(ε=9430)

Example 112 ##STR154##

IR(KBr)cm⁻¹ : 1749,1560,1394

¹ H-NMR(D₂ O)δ: 1.11(3 H,d,J=7.3 Hz),1.22(3 H,d,J=6.4 Hz),1.63-1.74(1H,m),2.59-2.72(1 H,m),3.22-3.36(2 H,m),3.37-3.49(2 H,m),3.51-3.60(1H,m),3.72-3.85(1 H,m),3.86-3.97(1 H,m),4.12-4.23(2 H,m),5.29(2H,s),7.23-7.41(4 H,m),7.45(2 H,d,J=8.7 Hz),8.33(1 H,s)

Example 113 ##STR155##

IR(KBr)cm⁻¹ : 3420,2970,1740,1645,1590,1515,1400,1340, 1315,1150,1080

¹ H-NMR(D₂ O)δ: 1.09(3 H,d,J=7.0 Hz),1.23(3 H,d,J=6.0 Hz),2.30-2.70(3H,m),2.92(3 H,s),3.10-3.40(3 H,m),3.65(1 H,m), 4.00-4.20(4H,m),7.40-7.60(3 H,m),7.70(1 H,m), 7.85(1 H,m),8.25(1 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=11100)

Example 114 ##STR156##

IR(KBr)cm⁻¹ : 3384,1749,1581,1396,1301,1151,1097,1079,777

¹ H-NMR(D₂ O)δ: 1.15-1.29(6 H,m),1.45(1 H,m),2.50(1 H,m), 2.95(1H,dd,J=3.8 & 12.8 Hz),3.24(3 H,s),3.15-3.45(5 H,m),3.73(1H,m),4.07-4.25(3 H,m), 7.56(2 H,d,J=8.6 Hz),7.84(2 H,d,J=8.6 Hz)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=11800)

Example 115 ##STR157##

IR(KBr)cm⁻¹ : 3430,2970,1750,1690,1550,1450,1390,1270, 1150,900

¹ H-NMR(D₂ O)δ: 1.04(3 H,d,J=7 Hz),1.24(3 H,d,J=7 Hz), 1.34(1H,m),2.47(1 H,m),2.88(2 H,d,J=7 Hz),3.15-3.25(2 H,m),3.37(1 H,m),3.53(1H,m),3.75-3.9(2 H,m),4.0-4.2(4 H,m),4.21(2 H,s),4.53(2 H,s),7.5-7.7(2H,m),7.9-8.0(2 H,m),8.02(1 H,s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 294 nm(ε=12700)

Example 116 ##STR158##

IR(KBr) cm⁻¹ : 3841,3426,2967,1749,1635,1542,1456,1394,1147

¹ H-NMR(D₂ O)δ: 1.09(3 H,d,J=7.1 Hz),1.25(3 H,d,J=6.4Hz),1.41-1.51(1H,m),2.43-2.55(1H,m),2.91-3.98(2H,m),3.16-3.27(2H,m),3.38-3.65(6 H,m),3.70-3.88(2 H,m),4.09-4.25(4 H,m),4.66(2H,s),7.50-7.61(2 H,m),7.86(1 H,s),7.90-7.98(2 H,m),7.99(1 H,s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=9130)

Example 117 ##STR159##

IR(KBr)cm⁻¹ : 3425,2967,1749,1679,1560,1456,1394,1267

¹ H-NMR(D₂ O)δ: 1.07(3 H,d,J=7.25 Hz),1.24(3 H,d,J=6.4 Hz), 1.35(1H,m),2.50(1 H,m),2.90(2 H,d),3.16-3.31(2 H,m),3.39(1 H,dd),3.55(1H,m),3.78-3.90(4 H,m),4.05-4.25(4 H,m),4.55(2 H,s),4.91(2 H,s),7.51-7.60(2 H,m),7.87-7.91(2 H,m),8.13(1 H,s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=11500)

Example 118

(1R,5S,6S)-2- (3S,5S)-5- 6-(4-Carbamoylmethyl-1,4-diazabicyclo2.2.2!octanedium-1-ylmethyl)naphthalen-2-ylmethylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic aciddichloride ##STR160##

To a solution of p-nitrobenzyl (1R,5S,6S)-6-(1R)-1-hydroxyethyl!-1-methyl-2- (3S,5S)-1-p-nitrobenzyloxycarbonyl-5-6-hydroxymethyl-2-ylmethylthiomethyl!pyrrolidin-3-ylthio!-1-carbapen-2-em-3-carboxylate(1.81 g, 2.14 mmol) obtained in accordance with the method described inExamples 1 to 5 in a mixture of THF (20 ml) and DMF (2 ml), TEA (0.36ml, 2.57 mmol) and then propanesulfonic acid chloride (0.33 ml, 2.57mmol) was added dropwise under cooling with ice. The resulting reactionsolution was stirred under cooling with ice for 30 minutes and pouredinto a liquid mixture of ethyl acetate and water. The organic layer waswashed successively with 1N aqueous potassium hydrogensulfate andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and concentrated in vacuo. To the solution of the resulting yellow oilin acetone (10 ml), sodium iodide (630 mg, 4.20 mmol) was added undercooling with ice. The resulting reaction solution was stirred at thesame temperature for 20 minutes, concentrated in vacuo, and poured intoa liquid mixture of ethyl acetate with water. The organic layer wasseparated, washed successively with 2% aqueous sodium thiosulfate andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and concentrated in vacuo. To a solution of the resulting yellow oil inacetonitrile (30 ml), 1-carbamoylmethyl-1,4-diazabicyclo2.2.2!octanedium trifluoromethanesulfonate (3.2 g, 10 mmol) was addedthereto. The resulting mixture was stirred at room temperature overnightand then the solvent was distilled off. To a solution of the residue ina mixture of 0.25 mol MOPS buffer (pH 7.0, 80 ml), THF (80 ml) andethanol (4 ml), 10% palladium carbon (2.0 g) was added. Catalyticreduction was conducted at room temperature under the atmosphericpressure of hydrogen for 4 hours. After the catalyst was filtered off,the filtrate was concentrated in vacuo. The resulting aqueous solutionwas washed with ethyl acetate and then concentrated in vacuo. To thesolution, sodium chloride was added and it was stirred for 10 minutes,and then the excess sodium chloride and the insolubles formed in smallamounts were filtered off. The filtrate was purified by reverse phasecolumn chromatography (14 ml, 1-2% aqueous THF solution) and lyophilizedto give the title compound (209 mg, yield: 13%).

IR(KBr)cm⁻¹ : 3444,2362,1747,1690,1651,1568,1541,1400

¹ H-NMR(D₂ O)δ: 1.11(3 H,d,J=7.3 Hz),1.27(3 H,d,J=6.7 Hz), 1.47(1H,m),2.60(1 H,m),2.88(2 H,m),3.27(2 H,m), 3.41(1 H,dd,J=2.7 & 6.0Hz),3.60(1 H,dd,J=6.6 & 12.5 Hz), 3.83(1 H,m),3.90(1 H,m),4.04(2H,s),4.11-4.30(14 H,m), 4.41(2 H,s),5.00(2 H,s),7.64(2 H,dd,J=8.2 & 10.2Hz), 7.94(1 H,s),8.07(2 H,dd,J=5.7 & 8.6 Hz),8.15(1 H,s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 290 nm(ε=12000)

In the following Examples 119 and 120, compounds represented by theformula (A) which have substituents R₁ and R₂ were synthesized in thesame manner as in Example 118. ##STR161##

Example 119 ##STR162##

IR(KBr)cm⁻¹ : 3361,1749,1697,1392,858,763

¹ H-NMR(D₂ O)δ: 1.06(3 H,d,J=7.0 Hz),1.23(3 H,d,J=6.4 Hz), 1.30(1H,m),2.38(1 H,m),2.82(2 H,m),3.18(2 H,m), 3.36(1 H,m),3.50(1 H,dd,J=6.5& 12.4 Hz),3.62(1 H,m), 3.78(1 H,m),4.10-4.21(14 H,m),4.37(2 H,s),5.15(2H,s), 7.67(2 H,m),7.97(3 H,m),8.19(1 H,s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=8640)

Example 120 ##STR163##

IR(KBr)cm⁻¹ : 3403,1743,1693,1647,1549,1407,1267

¹ H-NMR(D₂ O)δ: 0.93(3 H,d,J=7.3 Hz),1.12(3 H,d,J=7.0 Hz), 2.62(1H,m),3.20(2 H,m),3.39(2 H,m),3.66(2 H,m), 4.15(12 H,m),4.33(2H,m),4.57(2 H,s),7.64-8.20(6 H,m),1.20(1 H,m),2.90(2 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 295 nm(ε=9620)

Example 121

(1R,5S,6S)-2- (3S,5S)-5-4-(Aminomethyl)anilinomethyl!-pyrrolidin-3-ylthio!-6-(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acidmonohydrochloride ##STR164## (Step 1)

To a solution of (2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenxyloxycarbonyl)aminomethyl!anilinomethyl!-4-tritylthiopyrrolidine(1.55 g, 1.85 mmol) in methylene chloride (15 ml), trifluoroacetic acid(1.37 ml, 1.85 mmol) and triethylsilane (0.443 ml, 2.78 mmol) weresuccessviely added dropwise at 0° C. in a nitrogen steam. The reactionsolution was stirred for 3 hours, then diluted with water andchloroform, and adjusted to pH 6.7 with potassium carbonate. The organiclayer was washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, and then concentrated in vacuo to give acrude product of (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!anilinomethyl!-pyrrolidine.

To a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate (1.10 g, 1.85mmol) and the above crude product in acetonitrile (30 ml),N,N-diisopropylethylamine (0.644 ml, 3.70 mmol) was added dropwise in anitrogen stream under cooling with ice. The resulting reaction solutionwas stirred at the same temperature for 24 hours. Then, water was addedto terminate the reaction, and the mixed solution was extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium chloride and dried over anhydrous magnesium sulfate, andconcentrated in vacuo. The resulting residue was Subjected to silica gelcolumn chromatography (Wakogel™ C-300, ethyl acetate) to givep-nitrobenzyl (1R,5S,6S)-6- (R)-1-hydroxyethyl!-1-methyl-2- (3S,5S)-5-4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!-anilinomethyl!pyrrolidin-3-ylthio!-1-carbapen-2-em-3-carboxylate(913 mg, yield: 52.5%).

¹ H NMR(CDCl₃)δ: 1.28(3 H,d,J=6.8 Hz),1.37(3 H,d,J=6.2 Hz), 1.80-2.01(1H,m),2.54-2.69(1 H,m),3.25-3.41(4 H,m),3.43-3.73(2 H,m),3.80-4.60(6H,m),5.04-5.14(1 H,m),5.19-5.30(5 H,m),5.51(1 H,d,J=13.8 Hz),6.40-6.65(2H,m),6.94-7.11(2 H,m),7.51(2 H,d,J=8.7 Hz),7.65(2 H,d,J=8.8 Hz), 8.21(2H,d,J=8.7 Hz),8.21(2 H,d,J=8.8 Hz)

(Step 2)

To a solution of the compound (400 mg, 0.426 mmol) obtained in Step 1 intetrahydrofuran (30 ml), 0.2N sodium 3-morpholinopropanesulfonate buffer(15 ml, pH 6.5) and 10% palladium-carbon (400 mg) were added. Theresulting mixed solution was stirred vigorously in a hydrogen stream atroom temperature for 20 hours. After the catalyst was filtered off, theorganic solvent was concentrated in vacuo to obtain an aqueous solution.The insolubles were filtered off and then the filtrate was adjusted topH 7.0 with 1N aqueous sodium hydroxide. The solution was subjected toreverse phase column chromatography (YMC.GEL™ODS-AQ-120-S50, 14 ml,methanol-water 25:75). The fractions containing the desired product wereconcentrated and lyophilized to give the title compound (78.6 mg, yield:38.2%).

IR(KBr) cm⁻¹ : 1751,1614,1531,1389,1265

¹ H NMR(D₂ O)δ: 1.17(3 H,d,J=7.1 Hz),1.24(3 H,d,J=6.5 Hz), 1.69-1-82(1H,m),2.65-2.79(1 H,m),3.15-3.45(3 H,m),3.48-3.70(3 H,m),3.84-4.13(2H,m),4.02(2 H,s),4.14-4.23(2 H,m),6.79(2 H,d,J=8.6 Hz),7.26(2 H,d,J=8.6Hz)

In the following Examples 122 to 124, compounds represented by theformula (C) which have substituents R₅ and R₆ were synthesized in thesame manner as in Example 121.

    __________________________________________________________________________     ##STR165##                                                                   Ex.            IR (KBr)              Re-                                      No.                                                                              R.sub.5   R.sub.6                                                                         cm.sup.-1                                                                           .sup.1 H NMR (D.sub.2 O) δ                                                              marks                                    __________________________________________________________________________    122                                                                               ##STR166##                                                                             H 1755, 1600                                                                          1.21(3H, d, J=7.0Hz), 1.28(3H, d, J= 6.3Hz),                                  1.70-2.00(1H, m), 3.30- 3.50(4H, m), 3.50-3.60(2H,                            m), 3.70-3.80(4H, m), 3.90-4.10(1H, m),                                       4.20-4.30(1H, m), 6.70-6.90 (3H, m), 7.20-7.40(2H,                            m),             Mono- hydro- chloride                    123                                                                               ##STR167##                                                                             H 1749, 1589                                                                          0.80-1.00(1H, m), 1.21(3H, d, J= 7.1Hz), 1.28(3H, d,                          J=6.3Hz), 1.50- 2.50(3H, m), 2.70-3.10.(1H, m),                               3.20-3.50(4H, m), 3.50-3.70 (3H, m), 3.80-4.10(3H,                            m), 4.20-4.30 (2H, m), 6.8-7.0(1H, m), 7.2-7.4 (3H,                           m),             --                                       124                                                                               ##STR168##                                                                             H 1754, 1716, 1591                                                                    1.21(3H, d, J=7.4Hz), 1.28(3H, d, J= 6.4Hz),                                  1.70-1.90(1H, m), 2.70- 2.90(1H, m), 3.20-3.50 (4H,                           m), 3.50-3.70(3H, m), 3.90(3H, s), 4.00-4.10(2H, m),                          4.20-4.30(2H, m), 4.60-5.00(3H, m), 7.00-7.10 (1H,                            m), 7.30-7.50(3H, m),                                                                         --                                       __________________________________________________________________________

In the following Example 125, compounds represented by the formula (B)which have substituents R₃ and R₄ were synthesized in the same manner asin Example 121. ##STR169##

Example 125 ##STR170## Diastereomer A

IR(KBr)cm⁻¹ : 1741,1565,1340

¹ H-NMR(D₂ O)δ: 0.97(3 H,d,J=7 Hz),1.15(3 H,d,J=6 Hz), 4.05(2H,m),4.41(1 H,m),6.75-6.92(3 H,m),7.20-7.32(2 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0 ): 300 nm(ε=8630 )

Diastereomer B

IR(KBr)cm⁻¹ : 1739,1533,1402

¹ H-NMR(D₂ O)δ: 0.94(3 H,d,J=7 Hz),1.25(3 H,d,J=6 Hz), 4.20(2H,m),6.80-6.95(3 H,m),7.20-7.35(2 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=5080)

In the following Example 126, a compound represented by the formula (A)which has substituents R₁ and R₂ was synthesized in the same manner asin Example 121. ##STR171##

Example 126 ##STR172##

IR(KBr)cm⁻¹ : 3382,2967,1751,1583,1537,1446,1390

¹ H-NMR(D₂ O)δ: 1.13(3 H,d,J=6.3 Hz),1.22(3 H,d,J=6.3 Hz),1.75-1.89(1H,m),2.67-2.84(1 H,m),3.20-3.44(3 H,m),3.58-3.77(3 H,m),3.95-4.23(4H,m),4.50(2 H,s), 6.71(1 H,d,J=7.9 Hz),7.46(1 H,d,J=7.8 Hz),7.57-7.68(2H,m),7.97(1 H,d,J=8.3 Hz),8.08(1 H,d,J=8.2 Hz)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 300 nm(ε=13400)

Example 127

(1R,5S,6S)-2- (3S,5S)-5-4-(Aminomethyl)phenoxymethyl!-pyrrolidin-3-ylthio!-6-(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acidmonohydrochloride ##STR173## (Step 1)

To a solution of (2S,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!phenoxymethyl!-pyrrolidine (786mg, 1.23 mmol) in tetrahydrofuranmethanol (1:1, 20 ml), 1N aqueoussodium hydroxide (1.48 ml, 1.48 mmol) was added in a nitrogen streamunder cooling with ice. The reaction solution was stirred at 2 hours,and 1N hydrochloric acid (1.6 ml, 1.6 mmol) was added thereto. Theresulting mixed solution was extracted with ethyl acetate. The extractwas washed with saturated aqueous sodium chloride and dried overanhydrous sodium sulfate. The solvent was distilled off in vacuo toobtain a crude product of(2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!phenoxymethyl!-pyrrolidine.

To a solution of the above crude product and p-nitrobenzyl(1R,5S,6S)-2-diphenoxyphosphoryloxy-6-(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate (731 mg,1.23 mmol) in acetonitrile (20 ml), N,N-diisopropylethylamine (0.257 ml,1.48 mmol) was added dropwise in a nitrogen stream under cooling withice. The resulting mixed solution was stirred at the same temperaturefor 14 hours. To the reaction solution, water was added to terminate thereaction. And the mixed solution was extracted with ethyl acetate. Theextract was washed with saturated aqueous sodium chloride and then driedover anhydrous magnesium sulfate. The solvent was distilled off in vacuoand the resulting residue was subjected to silica gel chromatography(Wakogel™ C-300, heptane-ethyl acetate=1:9) to give p-nitrobenzyl(1R,5S,6S)-6- (R)-1-hydroxyethyl!-1-methyl-2-(3S,5S)-N-(p-nitrobenzyloxycarbonyl)-5- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!phenoxymethyl!-pyrrolidin-3-ylthio!-1-carbapen-2-em-3-carboxylate(947 mg, yield: 81.8%).

¹ H-NMR(CDCl₃)δ: 1.28(3 H,d,J=7.1 Hz),1.38(3 H,d,J=6.3 Hz), 2.10-2.27(1H,m),2.55-2.70(1 H,m),3.25-3.46(3 H,m),3.62-3.78(1 H,m),4.00-4.22(2H,m),4.23-4.36(2 H,m), 4.33(2 H,d,J=5.9 Hz),5.12-5.37(5 H,m), 5.51(1H,d,J=14.0 Hz),6.71-6.91(2 H,m),7.13-7.24(2 H,m),7.42-7.57(4 H,m),7.66(2H,d,J=8.8 Hz),8.07-8.30(4 H,m),8.21(2 H,d,J=8.8 Hz)

(Step 2)

To a solution of the compound (420 mg, 0.446 mmol) obtained in thepreceding step in tetrahydrofuran (30 ml), 0.2N sodium3-morpholinopropanesulfonate buffer (15 ml, pH 6.5) and 10%palladium-carbon catalyst (400 mg) were added. The resulting mixedsolution was stirred vigorously in a hydrogen stream at room temperaturefor 16 hours. The catalyst was separated from the reaction mixture byfiltration and the filtrate was concentrated in vacuo to obtain anaqueous solution. The insolubles were filtered off and the filtrate wasadjusted to pH 7.0 with 1N aqueous sodium hydroxide and then subjectedto reverse phase column chromatography (YMC.GEL™ODS-AQ-120-S50, 14 ml;methanol-water 3:7). The fractions containing the desired product wereconcentrated and lyophilized to give the title compound (109 mg, yield:54.4%).

IR(KBr)cm⁻¹ : 1753,1610,1516,1392,1248

¹ H-NMR(D₂ O)δ: 1.19(3 H,d,J=7.2 Hz),1.25(3 H,d,J=6.5 Hz), 1.85-1.97(1H,m),2.70-2.83(1 H,m),3.30-3.46(3 H,m), 3.68(1 H,dd,J1=12.0 Hz,J2=6.0Hz),4.00-4.30(5 H,m),4.10(2 H,s),4.35-4.41(1 H,m), 7.06(2 H,d,J=8.7Hz),7.39(2 H,d,J=8.7 Hz)

Example 128

(1R,5S,6S)-6- (R)-1-Hydroxyethyl!-1-methyl-2-(3S,5S)-5-(phenoxymethyl)pyrrolidin-3-ylthio!-1-carbapen-2-em-3-carboxylicacid ##STR174##

The title compound was prepared in the same manner as in Example 127.

IR(KBr)cm⁻¹ : 3400,1750,1590

¹ H-NMR(DMSO-d₆)δ: 1.09(3 H,d,J=6.7 Hz), 1.13(3 H,d,J=6.1Hz),2.35-2.53(2 H,m),2.78-2.85(1 H,m),3.10-3.25(2 H,m),3.30-3.80(3H,m),3.85-4.05(3 H,m),4.05-4.12(1 H,m),6.87-6.95(3 H,m),7.22-7.30(2 H,m)

In the following Example 129, compounds represented by the formula (B)which have substituents R₃ and R₄ were synthesized in the same manner asin Example 127. ##STR175##

Example 129 ##STR176## Diastereomer A

IR(KBr)cm⁻¹ : 1751,1597,1394

¹ H-NMR(D₂ O)δ: 1.15(3 H,d,J=7 Hz),1.26(3 H,d,J=6 Hz), 3.77(1H,m),4.20(1 H,m),5.30(1 H,m),7.08(7 H,m), 7.38(2 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 299 nm(ε=6790)

Diastereomer B

IR(KBr)cm⁻¹ : 1751,1596,1394

¹ H-NMR(D₂ O)δ: 1.00(3 H,d,J=7 Hz),1.08(3 H,d,J=6 Hz), 5.13(1H,m),6.97(3 H,m),7.31(2 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 296 nm(ε=6310)

Example 130

(1R,5S,6S)-2- (3S,5R)-5-(4-Aminomethylphenethyl)pyrrolidin-3-ylthio!-6-(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acidmonohydrochloride ##STR177## (Step 1)

To a solution of (2S,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!phenethyl!pyrrolidine (495 mg,0.777 mmol) in tetrahydrofuran-methanol (2:1, 15 ml), 1N aqueous sodiumhydroxide (1.5 ml, 1.5 mmol) was added in a nitrogen stream undercooling with ice. After this reaction solution was stirred at the sametemperature for 2 hours, 1N aqueous hydrochloric acid (2.0 ml, 2.0 mmol)was added thereto, and this mixed solution was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride and dried over anhydrous magnesium sulfate. The solvent wasdistilled off in vacuo to give a crude product of(2R,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!phenethyl!-pyrrolidine.

To a solution of the above crude product and p-nitrobenzyl(1R,5S,6S)-2-diphenoxyphosphoryloxy-6-(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate (460 mg,0.777 mmol) in acetonitrile (10 ml), N,N-diisopropylethylamine (0.176ml, 1.01 mmol) was added in a nitrogen stream under cooling with ice.The reaction solution was stirred for 12 hours, brought together withwater to terminate the reaction, and then extracted with ethyl acetate.The organic layer was washed with saturated aqueous sodium chloride anddried over anhydrous magnesium sulfate. The solvent was distilled off invacuo and the residue was subjected to silica gel chromatography(Wakogel™ C-300, heptane-ethyl acetate=1:4) to give p-nitrobenzyl(1R,5S,6S)-6- (R)-1-hydroxyethyl!-1-methyl-2-(3S,5R)-N-(p-nitrobenzyloxycarbonyl)-5- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!phenethyl!pyrrolidin-3-ylthio!-1-carbapen-2-em-3-carboxylate(512 mg, yield: 70.1%).

¹ H-NMR(CDCl₃)δ: 1.27(3 H,d,J=6.8 Hz),1.38(3E,d,J=6.0 Hz), 1.60-1.90(2H,m),2.10-2.70(4 H,m),3.20-3.45(3 H,m),3.50-3.66(1 H,m),3.89-4.50(4H,m),4.36(2 H,d,J=5.9 Hz),5.10-5.40(5 H,m),5.50(1 H,d,J=14Hz),7.00-7.30(4 H,m),7.40-7.60(4 H,m),7.65(2 H,d,J=8.6 Hz),8.10-8.40(6H,m)

(Step 2)

To a solution of the compound (306 mg, 0.326 mmol) obtained in thepreceding step in tetrahydrofuran (20 ml), 0.2M sodium3-morpholinopropanesulfonate buffer (10 ml, pH 6.5) and 10%palladium-carbon catalyst (300 mg) were added. This reaction solutionwas stirred vigorously in a hydrogen stream at room temperature for 16hours. The catalyst was separated from the reaction solution byfiltration and the filtrate was concentrated in vacuo to obtain anaqueous solution. The insolubles were filtered off and the filtrate wassubjected to reverse phase column chromatography(YMC.GEL™ODS-AQ-120-S50, 14 ml; methanol-water 35:75). The fractionscontaining the desired product were concentrated and lyophilized to givethe title compound (80.2 mg, yield: 51.1%).

IR(KBr)cm⁻¹ : 1751,1579,1392

¹ H-NMR(D₂ O)δ: 1.15(3 H,d,J=7.1 Hz),1.24(3 H,d,J=6.3 Hz), 1.56-1.70(1H,m),1.99-2.22(2 H,m),2.62-2.73(3 H,m),3.25-3.44(3 H,m),3.55-3.75(2H,m),3.90-4.00(1 H,m),4.12(2 H,s),4.10-4.26(2 H,m), 7.32(2 H,d,J=8.2Hz),7.37(2 H,d,J=8.2 Hz)

In the following Example 131 to 134, compounds represented by theformula (D) which have substituents R₇ and R₈ were synthesized in thesame manner as in Example 130.

    __________________________________________________________________________     ##STR178##                                                                   Ex.                     IR (KBr)              Re-                             No.   R.sub.7         R.sub.8                                                                         cm.sup.-1                                                                           .sup.1 H NMR (D.sub.2 O) δ                                                              marks                           __________________________________________________________________________    131                                                                                  ##STR179##     H 1756, 1585, 1388                                                                    1.20(3H, d, J=7.3Hz), 1.28(3H, d, J=6.4Hz),                                   1.80(1H, m), 2.20 (1H, m), 2.70(1H, m),                                       3.00(1H, t, J=7.3Hz), 3.20(1H, m), 3.22-                                      3.50(3H, m), 3.65(1H, m), 3.85-4.10(2H, m),                                   4.19(2H, s), 4.22(1H, m), 7.36-7.52(4H,                                                       Mono- hydro- chloride           132                                                                                  ##STR180##     H 1753, 1612, 1571, 1390                                                              1.21(3H, d, J=7.3Hz), 1.29(3H, d, J=6.3Hz),                                   1.80(1H, m), 2.70 (1H, m), 3.12-3.52(6H,                                      m), 3.65(1H, m), 3.90-4.10(2H, m), 4.20(2H,                                   s), 4.25(1H, m), 7.35-7.55(4H,                                                                Mono- hydro- chloride           133                                                                                  ##STR181##     H 1753, 1593                                                                          1.22(3H, d, J=7.1Hz), 1.29(3H, d, J=6.6Hz),                                   1.79(1H, m), 2.71 (1H, m), 3.18(2H, m),                                       3.40(4H, m), 3.63(2H, m), 3.98(2H, m),                                        4.22(2H, m), 7.37(15H, m)                                                                     --                              134                                                                                  ##STR182##     H 1750, 1590 1450                                                                     1.20(3H, d, J=7.3Hz), 1.29(3H, d, J=6.4Hz),                                   1.70-1.80(1H, m), 2.00-2.20(2H, m), 2.70-                                     2.80(3H, m), 3.30-3.40(2H, m), 3.50(1H, m),                                   3.60-3.70 (2H, m), 3.90-4.00(1H, m),                                          4.20-4.30(2H, m), 7.20-7.50 (5H,                                                              --                              __________________________________________________________________________

Example 135

(1R,5S,6S)-2-(3S,5R)-5-(4-Aminomethyl-1-naphthylmethyl)-pyrrolidin-3-ylthio!-6-(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acidmonohydrochloride ##STR183## (Step 1)

To a solution of (2R,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-4-(p-nitrobenzyloxycarbonylaminomethyl)-1-naphthylmethyl!pyrrolidine(144 mg, 0.21 mmol) in methanol-tetrahydrofuran (3:1) (4 ml), 1N aqueoussodium hydroxide (0.24 ml, 0.24 mmol) was added in a nitrogen streamunder cooling with ice. This reaction solution was stirred for 10minutes and then 1N hydrochloric acid (0.24 ml, 0.24 mmol) was addedthereto. Then the resulting solution was concentrated in vacuo. Theresulting residue was poured into a liquid mixture of ethyl acetate withwater. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, and concentrated in vacuoto give a crude product of(2R,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-4-(p-nitrobenzyloxycarbonylaminomethyl)-1-naphthylmethyl!-pyrrolidine asa yellow oily substance.

To a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-(1R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate (127 mg,0.21 mmol) in acetonitrile (3 ml), a solution of the above crude productin acetonitrile (2 ml) and N,N-diisopropylethylamine (45 μl, 0.26 mmol)were successively added dropwise in a nitrogen stream under cooling withice. The reaction solution was stirred at the same temperature for 18hours and then concentrated in vacuo. The resulting residue was pouredinto a liquid mixture of ethyl acetate with water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and concentrated in vacuo. The resulting residue wassubjected to silica gel column chromatography (Wakogel™ C-300,heptane-ethyl acetate 1:2) to give p-nitrobenzyl (1R,5S,6S)-6-(1R)-1-hydroxyethyl!-1-methyl-2- (3S,5R)-N-(p-nitrobenzyloxycarbonyl)-5-4-(p-nitrobenzyloxycarbonylaminomethyl)-1-naphthylmethyl!pyrrolidin-3-ylthio!-1-carbapen-2-em-3-carboxylate(173 mg, yield: 82.9%) as a yellow powder.

¹ H-NMR(CDCl₃)δ: 1.23(3 H,m),1.37(3 H,d,J=7.1 Hz),1.84(1 H,m), 2.16(1H,m),3.27(1 H,m),3.34(1 H,m),3.49(1 H,m), 3.63(1 H,m),3.81-4.10(2H,m),4.26(2 H,m),4.39(1 H,m), 4.82(2 H,m),5.24(4 H,m),5.32(1 H,m),5.51(1H,m), 7.22(2 H,m),7.33(1 H,m),7.51(5 H,m),7.64(2 H,m), 8.01(2H,m),8.19(5 H,m),8.51(1 H,m)

(Step 2)

To a solution of the compound (171 mg, 0.18 mmol) obtained in Step 1 intetrahydrofuran (15 ml), 0.2N sodium 3-morpholinopropanesulfonate buffer(5 ml, pH 6.4) and 10% palladium-carbon catalyst (60 mg) were added.This reaction solution was stirred vigorously at room temperature atatmospheric pressure in a hydrogen stream for 21 hours. The catalyst wasseparated from the reaction solution by filtration and the filtrate wasconcentrated in vacuo to an aqueous solution. After the insolubles werefiltered off, the filtrate was adjusted to pH 6.4 with 1N aqueous sodiumhydroxide and subjected to reverse phase column chromatography(YMC.GEL™ODS-AQ-20-S50, 14 ml methanol-water 2:8). The fractionscontaining the desired product were concentrated and lyophilized to givethe title compound (2.9 mg, yield: 3.4%).

IR(KBr)cm⁻¹ : 3386,1753,1591

¹ H-NMR(D₂ O)8: 0.98(3 H,d,J=7.1 Hz),1.10(3 H,d,J=7.0 Hz), 1.62(1H,m),2.40(1 H,m),3.16(4 H,m),3.44(4 H,m), 3.73(1 H,m),3.79(1 H,m),3.99(2H,m),7.42(2 H,m), 7.59(2 H,m),8.02(2 H,m)

Example 136

(5S,6S)-6- (R)-1-Hydroxyethyl!-2-(3S,5R)-5-(1-naphthylmethyl)pyrrolidin-3-ylthio!-1-carbapen-2-em-3-carboxylicacid ##STR184## (Step 1)

Allyl (5R,6S)-2-(3S,5S)-N-(allyloxycarbonyl)-5-(1-naphthylmethyl)pyrrolidin-3-ylthio!-6-(1R)-1-hydroxyethyl!-1-carbapen-2-em-3-carboxylate (633 mg, yield:70.1%) was prepared as a yellow powder, from(2R,4S)-4-acetylthio-N-allyloxycarbonyl-2-(1-naphthylmethyl)pyrrolidine(610 mg, 1.53 mmol), allyl (5R,6S)-2-diphenoxyphosphoryloxy-6-(1R)-1-hydroxyethyl!-1-carbapen-2-em-3-carboxylate (743 mg, 1.53 mmol),1N aqueous sodium hydroxide (1.8 ml, 1.8 mmol), 1N aqueous hydrochloricacid (1.8 ml, 1.8 mmol) and N,N-diisopropylethylamine (800 μl, 4.59mmol), in the same manner as in Example 135-1.

¹ H-NMR(CDCl₃)δ: 1.32(3 H,d,J=7.2 Hz),1.81(1 H,m),2.14(1 H,m), 3.03(4H,m),3.49(2 H,m),4.26(5 H,m),4.72(4 H,m), 5.36(4 H,m),6.01(2 H,m),7.46(4H,m),7.80(2 H,m), 8.36(1 H,m)

(Step 2)

To a solution of the compound (310 mg, 0.53 mmol) obtained in Step 1 indichloromethane (10 ml), water (47 μl),bis(triphenylphosphine)palladium(II) chloride (18 mg, 0.026 mmol) andtributyltin hydride (352 μl, 1.31 mmol) were added in a nitrogen streamunder cooling with ice. The resulting solution was stirred at the sametemperature for 20 minutes. The reaction mixture was extracted withwater (80 ml) and the aqueous layer was washed with chloroform twice.Then, the insolubles were filtered off. The filtrate was concentrated invacuo to about 30 ml and the resulting residue was subjected to reversephase column chromatography (YMC.GEL™ODS-AQ-120-S50 14 ml methanol-water1:1). The fractions containing the desired product were concentrated andlyophilized to give the title compound (15.0 mg, yield: 5.6%).

IR(KBr)cm^('1) : 1756,1592,1081

¹ H-NMR(DMSO-d₆)δ: 1.10(3 H,m),1.51(1 H,m),2.22(1 H,m), 2.88-4.09(11H,m),7.46(4 H,m),7.84(2 H,m),8.21(1 H,m)

Example 137

(1R,5S,6S)-2-(3S,5R)-N-Allyl-5-(1-naphthylmethyl)pyrrolidin-3-ylthio!-6-(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid##STR185## (Step 1)

Allyl (1R,5S,6S)-6- (1R)-1-hydroxyethyl!-2-(3S,5R)-N-(allyloxycarbonyl)-5-(1-naphthylmethyl)pyrrolidin-3-ylthio!-1-methyl-1-carbapen-2-em-3-carboxylate(564 mg, yield: 69.3%) was obtained from(2R,4S)-4-acetylthio-N-(allyloxycarbonyl)-2-(1-naphthylmethyl)pyrrolidine(536 mg, 1.34 mmol) and allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-(1R)-1-hydroxyethyl!-1-carbapen-2-em-3-carboxylate (670 mg, 1.34 mmol)in the same manner as in Example 135-1.

¹ H-NMR(CDCl₃)δ: 1.22(3 H,d,J=7.0 Hz),1.37(3 H,d,J=6.6 Hz), 2.12(1H,m),2.90(1 H,m),3.19-3.61(4 H,m),3.96-4.44(6 H,m),4.62-4.91(4H,m),5.21-5.50(4 H,m), 5.98(2 H,m),7.43(4 H,m),7.80(2 H,m),8.36(1 H,m)

(Step 2)

To a solution of the compound (564 mg, 0.93 mmol) obtained in Step 1 indichloromethane (20 ml), water (84 μl),bis(triphenylphosphine)palladium(II) chloride (35 mg, 0.05 mmol) andtributyltin hydride (576 μl, 2.14 mmol) were added in a nitrogen streamunder cooling with ice. The resulting solution was stirred at the sametemperature for 20 minutes and concentrated in vacuo. To the resultingresidue, 2.00 ml of water was added and the resulting aqueous solutionwas adjusted to pH 5.0 with 1N aqueous hydrochloric acid. This solutionwas subjected to reverse phase phase column chromatography(YMC.GEL™ODS-AQ-120-S50 methanol-water 1:1), and the fractionscontaining the desired product were concentrated and lyophilized to givethe title compound (104 mg, yield: 23%).

IR(KBr)cm⁻¹ : 1754,1592

¹ H-NMR(DMSO-d₆)δ: 1.03(3 H,d,J=6.8 Hz),1.14(3 H,d,J=6.6 Hz), 1.40(1H,m),1.96(1 H,m),2.40-4.10(12 H,m),5.20(2 H,m), 5.90(1 H,m),7.46(4H,m),7.82(2 H,m),8.06(1 H,m)

Example 138

(1R,5S,6S)-2- 5-(4'-Aminomethyl-4-biphenylmethyl)pyrrolidin-3-ylthio!-6-(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acidmonohydrochloride ##STR186##

The title compound was prepared in the same manner as in Example 135.

IR(KBr)cm⁻¹ : 1755,1628

¹ H-NMR(DMSO-d₆)δ: 0.80(3 H,d,J=6.6 Hz),0.87(3 H,d,J=6.0 Hz),1.40-1.43(1 H,m),2.29-2.34(1 H,m),2.79-3.06(5 H,m),3.22-3.29(1H,m),3.58-3.61(2 H,m),3.79-3.85(4 H,m),7.04-7.38(8 H,m)

In the following Example 139, compounds represented by the formula (B)which have substituents R₃ and R₄ were synthesized in the same manner asin Example 135. ##STR187##

Example 139 ##STR188## Diastereomer A

IR(KBr)cm⁻¹ : 1749,1652,1558

¹ H-NMR(D₂ O)δ: 1.22(3 H,d,J=7 Hz),1.27(3 H,d,J=6 Hz), 2.14(1H,m),3.00(1 H,m),3.39(1 H,m),3.46(2 H,m), 3.80(1 H,m),4.14(1 H,m),4.20(2H,s),4.24(1 H,m), 7.52(2 H,d,J=8 Hz),7.55(2 H,d,J=8 Hz)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 298 nm(ε=9910)

Diastereomer B

IR(KBr)cm⁻¹ : 1749,1646,1558

¹ H-NMR(D₂ O)δ: 1.22(3 H,d,J=7 Hz),1.27(3 H,d,J=6.5 Hz), 2.51(1H,m),2.73(1 H,m),3.30-3.50(3 H,m), 3.86(1 H,dd,J=12.5 & 6Hz),4.20-4.30(5 H,m), 5.03(1 H,dd,J=10.5 & 7 Hz),7.52(4 H,br s)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 298 nm(ε=9520)

Example 140

(1R,5S,6S)-2- (3S,5S)-5-4'-Aminomethyl-4-biphenyl!hydroxymethyl!pyrrolidin-3-ylthio!-6-(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acidmonohydrochloride diastereomer I ##STR189## (Step 1)

To a solution of (2S,4S)-4-acetylthio-2- hydroxy 4'-(p-nitrobenzyloxycarbonylamino)methyl!-4-biphenyl!methyl!-N-(p-nitrobenzyloxycarbonyl!pyrrolidinediastereomer I (385 mg, 0.57 mmol) in methanoldichloromethane (1:1, 20ml), 1N aqueous sodium hydroxide (0.63 ml, 0.63 mmol) was added in anitrogen stream under cooling with ice. This reaction solution wasstirred for 30 minutes and then 1N aqueous hydrochloric acid (0.63 ml,0.63 mmol) was added thereto. This reaction solution was poured into aliquid mixture of ethyl acetate with water. The organic layer was washedwith saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate, and concentrated in vacuo to give a crude product of (2S,4S)-2-hydroxy 4'-(p-nitrobenzyloxycarbonylamino)methyl!-4-biphenyl!methyl!-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidinediastereomer I. To a solution of the crude product in acetonitrile (13ml), p-nitrobenzyl (1R,5S,6S)-2-dipheonoxyphosphoryloxy-6-(R)-1-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylate (373.1 mg,0.63 mmol) and then N,N-diisopropylamine (0.13 ml, 0.74 mmol) was addedin a nitrogen stream under cooling with ice. The resulting reactionsolution was stirred at the same temperature for 18 hours and thenconcentrated in vacuo. The resulting residue was poured into a liquidmixture of ethyl acetate with water. The organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and then concentrated in vacuo. The resulting oily residue was subjectedto silica gel column chromatography (Wakogel™ C-300, 60 ml; ethylacetate) to give p-nitrobenzyl (1R,5S,6S)-6- (R)-1-hydroxyethyl!-2-(3S,5S)-5- hydroxy 4'-(p-nitrobenzyloxycarbonylamino)methyl!-4-biphenyl!methyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio!-1-methyl-1-carbapen-2-em-3-carboxylatediastereomer I (434 mg, yield: 74.8%) as a pale yellow oily substance.

IR(KBr)cm⁻¹ : 2969,2362,1770,1704,1521

¹ H-NMR(CDCl₃)δ: 1.22-1.25(3 H,m),1.38(3 H,d,J=6.3 Hz),1.71-1.75(1H,m),2.09-2.26(2 H,m),3.12-3.51(4 H,m),4.22-4.46(5 H,m),5.20-5.62(8H,m),7.35-7.69(14 H,m),8.20-8.27(6 H,m)

(Step 2)

To a solution of the compound (430 mg, 0.42 mmol) obtained in Step 1 intetrahydrofuran (40 ml), ethanol (20 ml), 0.1N sodium3-morpholinopropanesulfonate buffer (20 ml, pH 6.5) and then 10%palladium carbon catalyst (150 mg) were added. Then, the reactionmixture was stirred vigorously in a hydrogen stream under pressure (45psi) for 16 hours. The catalyst was separated from the reaction mixtureby filtration. The filtrate was adjusted to pH 5.0 with 0.1N aqueoushydrochloric acid and then concentrated in vacuo to obtain an aqueoussolution. The insolubles were filtered off and the filtrate wassubjected to reverse phase column chromatography(YMC.GEL™ODS-AQ-120-S50, 14 ml acetonitrile-water=1:9). The fractionscontaining the desired compound were concentrated and lyophilized togive the title compound (137 mg, yield: 57.9%).

IR(KBr)cm⁻¹ : 3781,2973,1751,1735,1491

¹ H-NMR(D₂ O)δ: 0.79(3 H,d,J=7.3 Hz),0.88(3 H,d,J=6.3 Hz),1.57-1.65(1H,m),2.08-2.15(1 H,m),2.91-3.07(3 H,m),3.28-3.35(1 H,m),3.57-3.85(6H,m),4.78-4.80(2 H,m),7.16-7.41(8 H,m)

In the following Examples 141 to 148, compounds represented by theformula (D) which have substituents R₇ and R₈ were synthesized in thesame manner as in Example 140.

    __________________________________________________________________________    Ex.                                                                           No.                                                                              R.sub.7         R.sub.8                                                                         IR (nujol)                                                                          .sup.1 H-NMR (D.sub.2 O) δ                                                              Remarks                            __________________________________________________________________________     ##STR190##                                                                   141                                                                               ##STR191##     H 1749, 1583                                                                          1.21(3H, d, J=7.2Hz), 1.29 (3H, d, J=6.6Hz),                                  1.96(1H, m), 2.51(1H, m), 3.35(2H, m),                                        3.48(1H, m), 3.64(2H, m), 4.04(2H, m),                                        4.23(4H, m), 7.53(8H, m)                                                                      Mono- hydro- chloride              142                                                                               ##STR192##     H 1751, 1587                                                                          1.16(3H, d, J=7.1Hz), 1.29 (3H, d, J=6.6Hz),                                  2.21(1H, m), 3.40(3H, m), 3.62(3H, m), 3.91                                   (3H, m), 4.21(3H, m), 7.74(4H, m), 8.20(2H,                                                   Single substance Mono- hydro-                                                 chloride                           143                                                                               ##STR193##     H 1755, 1593                                                                          1.21 (6H, m), 1.97(1H, m), 2.34(1H, m),                                       3.01-4.30(9H, m), 5,20(1H, m), 7.66(3H, m),                                   8.02(4H, m)     --                                 144A                                                                              ##STR194##     H 1756, 1571, 1390                                                                    1.21(3H, d, J=6.0Hz), 1.30(3H, d, J=4.6Hz),                                   2.00(1H, m), 2.50(1H, m), 3.30-3.45(2H, m),                                   3.48(1H, m), 3.72(1H, m), 4.00(1H, m), 4.12                                   (1H, m), 4.20-4.35(4H, m), 5.19 (1H, d,                                       J=6.0Hz), 7.45-7.60(4H, m)                                                                    Diastereomer A polar substance                                                onohydro- chloride                 144B                                                                              ##STR195##     H 1749, 1675, 1392                                                                    1.20(3H, d, J=7.2Hz), 1.30(3H, d, J=6.6Hz),                                   1.75(1H, m), 2.40(1H, m), 3.36(1H, m),                                        3.40-3.55(2H, m), 3.74(1H, m), 3.95-4.20(2H,                                  m), 4.20-4.30(4H, m), 7.48-7.60 (4H,                                                          Diastereomer B less polar                                                     substance Monohydro- chloride      145A                                                                              ##STR196##     H 1749, 1577, 1392                                                                    1.27(3H, d, J=7.4Hz), 1.33(3H, d, J=6.4Hz),                                   2.10(1H, m), 2.75(1H, m), 3.20(1H, m),                                        3.40-3.60(3H, m), 3.80-4.10(2H, m), 4.20-4.35                                 (3H, m), 4.45(1H, d, J=13.7Hz), 5.12(1H, d,                                   J=8.0Hz), 7.52(2H, d, J=4.0Hz), 7.55-7.70(2H,                                 m)              Diastereomer A polar substance                                                onohydro- chloride                 145B                                                                              ##STR197##     H 1749, 1589, 1386                                                                    1.23(3H, d, J=7.1Hz), 1.33(3H, d, J=6.3Hz),                                   1.65(1H, m), 2.50(1H, m), 3.30-3.55(3H, m),                                   3.75(1H, m), 4.05(1H, m), 4.20-4.35(3H, m),                                   4.42(2H, s), 5.22(1H, d, J=9.3 Hz),                                           7.50-7.65(4H, m)                                                                              Diastereomer B less polar                                                     substance                          146                                                                               ##STR198##     H 1751, 1587, 1145                                                                    1.10(3H, d, J=7.4Hz), 1.20(3H, d, J=6.3Hz),                                   1.60(0.3H, m), 1.85 (0.7H, m), 2.35(1H, m),                                   3.28-3.40 (3H, m), 3.60(1H, m), 3.80-4.05 (2H,                                m), 4.08-4.25(4H, m), 4.90 (0.3H, d, J=8.7Hz),                                5.08(0.7H, d, J= 5.4Hz), 9.83(4H,                                                             Monohydrochloride Diastereomer                                                A (polar substance): Diastereom                                               er B (less polar substance) =                                                 3:7                                 ##STR199##                                                                   146A                                                                              ##STR200##     H 1747, 1648, 1548                                                                    1.14(3H, d, J=6.6Hz), 1.23(3H, d, J=6.0Hz),                                   1.88-1.92(1H, m), 2.43-2.48(1H, m), 3.26-3.41                                 (3H, m), 3.60-4.05(3H, m), 4.15-4.21(4H, m),                                  5.11(1H, d, J=4.8Hz), 7.48(4H,                                                                Diastereomer A polar substance                                                onohydrochloride                   146B                                                                              ##STR201##     H 1753, 1599, 1392                                                                    1.19(3H, d, J=7.3Hz), 1.30(3H, d, J=6.3Hz),                                   1.73(1H, m), 2.39(1H, m), 3.25-3.50(3H, m),                                   3.60- 3.80(1H, m), 3.90-4.13(2H,                                              m), 4.14-4.35(4H, m), 5.00(1H, d, J= 8.5Hz),                                  7.54(4H, br)    Diastereomer B less polar                                                     substance Monohydrochloride        147                                                                               ##STR202##     H 3460, 1755, 1593                                                                    1.20(3H, m), 1.29(3H, d, J=7.4Hz), 1.70-2.04(1H                               , m), 2.20-2.62 (1H, m), 3.40(4H, m), 3.69(1H,                                m), 4.00(2H, m), 4.23(2H, m), 7.46 (5H, m),                                   5.01(1H, m)     --                                 __________________________________________________________________________

In the following Example 148, a compound represented by the formula (A)which have substituents R₁ and R₂ was synthesized in the same manner asin Example 140. ##STR203##

Example 148 ##STR204##

IR(KBr)cm⁻¹ : 1755,1582,1392

¹ H-NMR(D₂ O)δ: 1.21(3 H,d,J=7 Hz),1.31(3 H,d,J=6.5 Hz), 1.77(1H,m),2.57(1 H,m),3.39(1 H,m),3.46(2 H,m), 3.73(1 H,dd,J=12 & 6.5Hz),4.03(1 H,m),4.15-4.30(5 H,m), 5.26(1 H,d,J=8 Hz),7.29(1 H,t,J=9Hz),7.55(1 H,m), 7.62(1 H,m)

UVλ_(max) (0.1M MOPS buffer, pH7.0): 299 nm(ε=9460)

Reference Example 1

(2S,4S)-4-Mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(phenylthiomethyl)pyrrolidine##STR205## (Step 1)

To a solution of(2S,4S)-2-mesyloxymethyl-N-(p-nitrobenzyloxycarbonyl)-4-tritylthiopyrrolidine(9.6 g, 15.2 mmol) in THF (190 ml), thiophenol (2.34 ml, 22.8 mmol) and1,8-diazabicyclo 5.4.0!-7-undecene (3.4 ml, 22.8 mmol) were successivelyadded dropwise in a nitrogen stream under cooling with ice. The reactionsolution was stirred at room temperature for 15 minutes and the solventwas distilled off. To the residue, ethyl acetate was added. The organiclayer was washed with 1N aqueous potassium hydrogensulfate and saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The resulting residue was subjected to silica gelcolumn chromatography (Wakogel™ C-300 heptane-ethyl acetate 3:1) to give(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-phenylthiomethyl-4-tritylthiopyrrolidine(9.24 mg, yield: 94%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ: 1.58(1 H,s),1.65-1.95(1 H,m),2.00-2.15(1H,m),2.65-3.17(3 H,m),3.20-3.55(1 H,m),4.90-5.10(2 H,m),7.05-7.55(22H,m),8.07-8.30(2 H,m)

IR(KBr)cm⁻¹ : 3056,1702,1604,1521,1440,1346,1103,742

(Step 2)

To a solution of the compound (1.8 g, 2.78 mmol) obtained in Step 1 indichloromethane (18 ml), trifluoroacetic acid (18 ml) was added dropwisein a nitrogen stream under cooling with ice, and then triethylsilane(0.32 ml, 3.06 mmol) was added thereto. The reaction solution wasstirred for 1 hour. The solvent was distilled off and then ethyl acetatewas added to the residue. The resulting solution was washed with 1Mphosphate buffer (pH 5.5) and saturated aqueous sodium chloride, driedover anhydrous sodium sulfate, and concentrated in vacuo. The residuewas subjected to silica gel column chromatography (Wakogel™ C-300heptane-ethyl acetate 5:1) to give the title compound (1.07 g, yield:95%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ: 1.50-2.00(3 H,m),3.05-3.65(3 H,m),3.90-4.20(2H,m),5.05-5.20(2 H,m),7.05-7.50(7 H,m),8.10-8.25(2 H,m)

Reference Example 2

(2S,4S)-4-Acetylthio-1-p-nitrobenzyloxycarbonyl-2-(4-sulfamoylphenyl)thiomethlpyrrolidine##STR206## (Step 1)

To a liquid mixture of a solution of(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-mesyloxymethylpyrrolidine(5.02 g, 12.3 mmol) and p-mercaptobenzenesulfonamide (2.39 g, 12.6 mmol)in THF (60 ml) with -N,N-dimethylformamide (20 ml), 1,8-diazabicyclo5.4.0!-7-undecene (2.46 ml, 16.4 ml) was added dropwise in a nitrogenstream at room temperature. The reaction solution was stirred at thesame temperature for 7 hours and then poured into a liquid mixture ofethyl acetate with water. The organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated in vacuo. The resulting residue was subjected to silica gelcolumn chromatography (Wakogel™ C-300 heptane-ethyl acetate 9:1→4:1→3:2)to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-sulfamoylphenyl)thiomethylpyrrolidine(2.65 g, yield: 43.1%) as a colorless oily substance.

IR(KBr)cm⁻¹ : 3336,3255,2929,1683,1579

¹ H-NMR(CDCl₃)δ: 0.05(6 H,s),0.85(9 H,s),1.45(9 H,s),1.85-2.15(2H,m),2.96-3.15(1 H,m),3.28-3.60(3 H,m),4.10-4.42(2 H,m),4.72-4.86(2 H,brs),7.38-7.58(2 H,m),7.75-7.85(2 H,m)

(Step 2)

A solution of the compound (2.65 g, 5.28 mmol) obtained in Step 1 in5.4N hydrogen chloride-methanol (40 ml) was stirred at room temperaturefor 18 hours. This reaction solution was concentrated in vacuo and theresulting residue was dissolved in a liquid mixture of dioxane (25 ml)with water (25 ml). This solution was adjusted to pH 8.0 with 5N and 1Naqueous NaOH under cooling with ice. To this solution, sodiumhydrogencarbonate (1.11 g, 13.2 mmol) was added at room temperature, andthen a solution of p-nitrobenzyloxycarbonyl chloride (2.28 g, 10.6 mmol)in dioxane (5 ml) was added dropwise. This reaction solution was stirredat room temperature for 2 hours and then concentrated in vacuo. Theresulting residue was extracted with ethyl acetate. The organic layerwas washed successively with water and saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, and concentrated invacuo. The resulting residue was subjected to silica gel columnchromatography (Wakogel™ C-300 ethyl acetate) to give(2S,4R)-4-hydroxy-N-p-nitrobenzyloxycarbonyl-2-(4-sulfamoylphenyl)thiomethylpyrrolidine(2.12 g, yield: 86.0%) as a pale yellow oily substance.

IR(KBr)cm⁻¹ : 3367,3264,2942,1683

¹ H-NMR(DMSO-d₆)δ: 1.80-2.10(2 H,m),3.03-3.61(4 H,m),3.94-4.16(1H,m),4.20-4.13(1 H,m),4.94-5.05(1 H,m),5.15-5.30(1 H,m),7.23-7.73(8H,m),8.23(2 H,d,J=8.9 Hz)

(Step 3)

To a solution of the compound (2.09 g, 4.48 mmol) obtained in Step 2 andtriethylamine (0.75 ml, 5.38 mmol) in THF (50 ml), mesyl chloride (0.35ml 4.52 mmol) was added dropwise in a nitrogen stream under cooling withice. This reaction solution was stirred at the same temperature for 40minutes. Then, triethylamine (0.2 ml, 1.43 mmol) and mesyl chloride(0.11 ml, 1.42 mmol) were added thereto, and the resulting reactionsolution was stirred under cooling with ice for 20 minutes. Afteraddition of ethyl acetate (100 ml), the reaction solution was washedsuccessively with water and saturated aqueous sodium chloride, driedover anhydrous sodium sulfate, and concentrated in vacuo. The resultingresidue was dissolved in N,N-dimethylformamide (30 ml) and the resultingsolution was stirred in a nitrogen stream under heating at 60° C. Tothis solution, potassium thioacetate (780 mg, 6.84 mmol) was added andthis reaction solution was stirred at the same temperature for 7 hours.After addition of ethyl acetate, the reaction solution was washedsuccessively with water, saturated sodium hydrogencarbonate, water andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and concentrated in vacuo. The resulting residue was subjected to silicagel column chromatography (Wakogel™ C-300 heptane-ethyl acetate 4:1) togive(2S,4S)-4-acetylthio-1-p-nitrobenzyloxycarbonyl-2-(4-sulfamoylphenyl)thiomethylpyrrolidine(1.51 g, yield: 64.4%) as a pale yellow oily substance.

IR(KBr)cm⁻¹ : 3365,3261,1697,1521

¹ H-NMR(DMSO-d₆)δ: 1.75-1.95(1 H,m),2.33(3 H,s),3.07-3.38(2H,m),3.48-3.70(1 H,m),3.75-4.20(4 H,m),5.15-5.32(2 H,m),7.32(2 H,brs),7.37-7.76(6 H,m),8.23(2 H,d,J=8.9 Hz)

Reference Example 3

(2S,4S)-1-Allyloxycarbonyl-2-4-(2-allyloxycarbonylaminoethylthio)phenylthiomethyl!-4-tritylthiopyrrolidine##STR207## (Step 1)

To a solution of(2S,4S)-1-allyloxycarbonyl-2-mesyloxymethyl-4-tritylthiopyrrolidine(12.8 g, 23.8 mmol) and 4-(2-hydroxyethylthio)thiophenol (4.47 g, 25.6mmol) in THF (100 ml), 1,8-diazabicyclo 5.4.0!-7-undecene (4.11 ml, 26.1mmol) was gradually added dropwise in a nitrogen stream. This reactionsolution was stirred at room temperature overnight and then the solventwas distilled off in vacuo. The residue was extracted with ethylacetate. This ethyl acetate solution was washed successively with water,10% aqueous citric acid and saturated aqueous sodium chloride, driedover anhydrous sodium sulfate, and concentrated in vacuo. The resultingoily residue was subjected to silica gel column chromatography (Wakogel™C-300 heptane-ethyl acetate 2:1→1:1) to give(2S,4S)-1-allyloxyarbonyl-2-4-(2-hydroxyethylthio)phenylthiomethyl!-4-tritylthiopyrrolidine (9.67 g,yield: 65%).

IR(KBr)cm⁻¹ : 3428,1697,1442,1405,1353,1195,1106,746,702

¹ H-NMR(CDCl₃)δ: 1.76(1 H,m),2.18(1 H,m),2.70-2.90(4 H,m), 3.06(2H,t,J=6.0 Hz),3.30(1 H,m),3.72(2 H,t,J=6.0 Hz), 3.78(1 H,m),4.45(2H,m),5.23(2 H,m),5.85(1 H,m),7.20-7.50(15 H,m)

(Step 2)

To a solution of the compound (7.53 g, 12.0 mmol) obtained in Step 1 indichloromethane, mesyl chloride (0.975 ml, 12.6 mmol) and triethylamine(1.93 ml, 13.8 mmol) were successively added under cooling with ice. Theresulting reaction solution was stirred at 0° C. for 30 minutes. Thereaction solution was washed with water and saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, and concentrated in vacuoto give a foamy solid (8.10 g).

This foamy solid was dissolved in dimethyl sulfoxide (40 ml). To thissolution, sodium azide (purity 90%, 2.60 g, 36 mmol) was added. Theresulting reaction solution was stirred for 2 hours under heating atfrom 50° C. to 60° C. and then poured into ethyl acetate. The organiclayer was washed with water and saturated aqueous sodium chloride, driedover anhydrous sodium sulfate, and concentrated in vacuo. The resultingoily residue was subjected to silica gel column chromatography (Wakogel™C-300 heptane-ethyl acetate 5:1→4:1→3:1) to give(2S,4S)-1-allyloxycarbonyl-2-4-(2-azidoethylthio)phenylthiomethyl!-4-tritylthiopyrrolidine (6.65 g,yield: 85%) as a colorless oily substance.

IR(KBr)cm⁻¹ : 2100,1697,1405,1349,1319,1197,1105,744,702

¹ H-NMR(CDCl₃)δ: 1.72(1 H,m),2.18(1 H,m),2.70-3.00(4 H,m), 3.03(2H,t,J=7.0 Hz),3.41(2 H,t,J=7.0 Hz),3.51(1 H,m), 3.81(1 H,m),4.45(2H,m),5.21(2 H,m),5.85(1 H,m),7.10-7.50(15 H,m)

(Step 3)

To a solution of the compound (3.26 g, 5.0 mmol) obtained in Step 2 inTHF (50 ml), triphenylphosphine (1.38 g, 5.25 mmol) and water (135 mg,7.5 mmol) were added and the resulting reaction solution was stirred atroom temperature overnight. To this reaction solution, triethylamine(0.91 ml, 6.5 mmol) and allyl chloroformate (0.64 ml, 6.0 mmol) wereadded under cooling with ice and the reaction solution was stirred atthe same temperature for 1 hour. The reaction solution was concentratedin vacuo and the resulting residue was extracted with ethyl acetate.This ethyl acetate solution was washed successively with water andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and concentrated in vacuo. The resulting residue was subjected to silicagel column chromatography (Wakogel™ C-300 heptane-ethyl acetate4:1→3:1→2:1) to give (2S,4S)-1-allyloxycarbonyl-2-4-(2-allyloxycarbonylaminoethylthio)phenylthiomethyl!-4-tritylthiopyrrolidine(1.53 g, yield: 43%).

IR(KBr)cm⁻¹ : 1716,1697,1405,1353,1321,1249,1197,1141,1105,989,929,811,744,702

¹ H-NMR(CDCl₁₃)δ: 1.75(1 H,m),2.20(1 H,m),2.70-3.00(4 H,m), 3.00(2H,t,J=6.2 Hz),3.33(2 H,t,J=6.2 Hz),3.50(1 H,m), 3.79(1 H,m),4.40-4.60(4H,m),5.10(1 H,br m),5.20-5.30(4 H,m),5.80-6.00(2 H,m),7.20-7.50(15 H,m)

Reference Example 4

(2S,4S)-4-Acetylthio-4-allyloxycarbonyl-2-(3-allyloxycarbonylaminomethyl-4-chlorophenyl)thiomethylpyrrolidine##STR208## (Step 1)

To a mixed solution of(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-mesyloxymethylpyrrolidine(6.43 g, 15.7 mmol) in a mixture of THF (50 ml) withN,N-dimethylformamide (50 ml), (4-chloro-3-hydroxy)thiophenol (2.74 g,15.7 mmol) and 1,8-diazabicyclo 5.4.0!-7-undecene (2.82 ml, 18.8 mmol)were successively added in a nitrogen stream. The resulting reactionsolution was stirred at room temperature for 14 hours and then pouredinto a liquid mixture of ethyl acetate with water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, and concentrated in vacuo. The resulting oily residuewas subjected to silica gel column chromatography (Wakogel™ C-300heptane-ethyl acetate 8:1→4:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-chloro-3-hydroxymethyl)phenylthiomethylpyrrolidine(7.12 g, yield: 87.5%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ: 0.05(6 H,s),0.80(9 H,s),1.20-1.30(2 H,m), 1.39(9H,s),1.90-2.15(3 H,m),3.10-3.55(3 H,m),4.00-4.80(3 H,m),7.10-7.50(3 H,m)

(Step 2)

To a solution of the compound (1.33 g, 2.72 mmol) obtained in Step 1 inTHF (25 ml), triethylamine (417 μl, 2.99 mmol) and mesyl chloride (232μl, 2.99 mmol) were successively added in a nitrogen stream undercooling with ice. The resulting reaction solution was stirred at thesame temperature for 15 minutes. To the reaction solution, saturatedaqueous ammonium chloride was added and the organic layer was washedwith saturated aqueous sodium chloride and dried over anhydrousmagnesium sulfate. Then the solvent was distilled off in vacuo to give acrude mesyl derivative.

To a solution of the crude mesyl derivative in dimethyl sulfoxide (10ml), sodium azide (530 mg, 8.16 mmol) was added. The resulting reactionsolution was stirred at 70° C. in a nitrogen stream for 2 hours. Thereaction solution was poured into water (100 ml) and extracted withethyl acetate (50 ml×3). The organic layers were combined, then washedwith saturated aqueous sodium chloride, and dried over anhydrousmagnesium sulfate. The solvent was distilled off in vacuo to obtain ayellow residue containing(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(3-azidomethyl-2-chloro)phenylthiomethylpyrrolidine.

To a solution of the residue in THF (10 ml), water (73 μl, 4.08 mmol)and triphenylphosphine (1.07 g, 4.08 mmol) were successively added. Theresulting reaction solution was stirred at room temperature for 14 hoursand concentrated in vacuo. After addition of 1.75N hydrogenchloride-methanol solution (32 ml), the reaction solution was stirred atroom temperature for 14 hours and concentrated in vacuo to give a yellowresidue. A solution of the residue in dioxane-water (2:1, 50 ml) wasadjusted to pH 8.5 with 5N aqueous NaOH. To this solution, a solution ofallyl chloroformate (787 μl, 6.53 mmol) in dioxane (5 ml) was addeddropwise under cooling with ice, while the reaction solution wasmaintained at pH 8.0-9.0 by using 5N aqueous NaOH. The reaction solutionwas poured into a liquid mixture of ethyl acetate-water. The organiclayer was washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, and concentrated in vacuo. The resultingresidue was subjected to silica gel column chromatography (Wakogel™C-300 heptane-ethyl acetate 4:1→1:1) to give(2S,4R)-N-allyloxycarbonyl-4-hydroxy-2-3-(N-allyloxycarbonylaminomethyl)-4-chloro!phenylthiomethylpyrrolidine(1.85 g, yield: 100%).

¹ H-NMR(CDCl₃)ε: 2.80-3.90(7 H,m),4.40-4.70(5 H,m),5.20-5.40(4H,m),5.80-6.00(2 H,m),7.20-7.50(3 H,m)

(Step 3)

To a solution of the compound (1.85 g, 2.7 mmol) obtained in Step 2 inTHF (10 ml), triethylamine (376 μl, 2.7 mmol) and mesyl chloride (209μl, 2.7 mmol) were successively added in a nitrogen stream under coolingwith ice and the resulting reaction solution was stirred at the sametemperature for 15 minutes. To the reaction solution, saturated aqueousammonium chloride was added. The organic layer was washed with saturatedaqueous sodium chloride and dried over anhydrous magnesium sulfate. Thesolvent was distilled off in vacuo to give a crude mesyl derivative.

To a solution of the the crude mesyl derivative in N,N-dimethylformamide(10 ml), potassium thioacetate (461 mg, 4.05 mmol) was added and theresulting reaction solution was stirred at 70° C. for 3 hours. To thereaction solution, water was added and then the organic layer was washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and concentrated in vacuo. The resulting oily residue wassubjected to silica gel column chromatography (Wakogel™ C-300heptane-ethyl acetate 5:1→2:1) to give(2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(3-allyloxycarbonylaminomethyl-4-chlorophenyl)thiomethylpyrrolidine(960 mg, yield: 69.0%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ: 1.90-2.20(2 H,m),2.34(3 H,s),2.50-4.20(5H,m),4.40-4.70(5 H,m),5.20-5.40(4 H,m),5.80-6.00(2 H,m),7.20-7.50(3 H,m)

Reference Example 5

(2S,4S)-4-Acetylthio-2-(4-p-nitrobenzyloxycarbonylaminomethyl-2-sulfamoyl)phenylthiomethyl!-1-p-nitrobenzyloxycarbonylpyrrolidine##STR209## (Step 1)

To a solution of(2S,4R)-2-acetylthiomethyl-N-t-butoxycarbonyl-4-t-butyldimethylsiloxypyrrolidine(3.9 g, 10 mmol) in methanol (50 ml), 1N aqueous NaOH (11.0 ml, 11 mmol)was added in nitrogen stream under cooling with ice. The resultingsolution was stirred for 30 minutes, then brought together with 1Naqueous HCl (12.0 ml, 12 mmol), and concentrated in vacuo. The resultingresidue was poured into a liquid mixture of ethyl acetate with water.The organic layer was washed with saturated aqueous sodium chloride, anddried over anhydrous magnesium sulfate, and concentrated in vacuo togive a crude product of(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-mercaptomethylpyrrolidine.

To a solution of the above crude product in hexamethylphosphoramide (20ml), 440 mg (11 mmol) of 60% oily sodium hydride was added in a nitrogenstream under cooling with ice. To the solution which was stirred for 10minutes, methyl 4-chloro-3-sulfamoyl-1-benzoate (2.75 g, 11 mmol) wasadded. The reaction solution was stirred at the same temperatureovernight and poured into a liquid mixture of ethyl acetate with water.The organic layer was washed with saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, and concentrated in vacuo. Theresulting residue was subjected to silica gel column chromatography(Wakogel™ C-300 ethyl acetateheptane 1:4→2:5) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-methoxycarbonyl-2-sulfamoyl)phenylthiomethylpyrrolidine(3.84 g, yield: 68.4%) as a pale yellow oily substance.

IR(KBr)cm⁻¹ : 3369,3267,2954,1724,1686

¹ H-NMR(CDCl₃)δ: 0.04(6 H,s),0.84(9 H,s),1.44(9 H,s),1.90-2.20(2H,m),3.10-3.25(1 H,m),3.39(2 H,d,J=3.4 Hz), 3.60(1 H,dd,J=3.4 & 13.0Hz),3.91(3 H,s),4.20-4.40(1 H,m),4.35(1 H,t,J=3.8 Hz),5.41(2 H,s),7.26(1H,d,J=9.0 Hz),8.09(1 H,d,J=9.0 Hz),8.59(1 H,s)

(Step 2)

To a suspension of lithium aluminum hydride (207 mg, 5.46 mmol) in ether(60 ml), a solution of the compound (1.02 g, 1.82 mmol) obtained in Step1 in ether (20 ml) was added dropwise in a nitrogen stream under coolingwith ice and the resulting reaction solution was stirred for 1 hour. Tothe reaction solution which was diluted with ether (30 ml) sodiumsulfate decahydrate (3.52 g, 10.9 mmol) was gradually added and thereaction solution was stirred at room temperature overnight. Theinsolubles were filtered off and the filtrate was concentrated in vacuo.The resulting residue was subjected to silica gel column chromatography(Wakogel™ C-300 ethyl acetate-heptane 2:3) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-hydroxymethyl-2-sulfamoyl)phenylthiomethylpyrrolidine(860 mg, yield: 88.7%) as white crystals.

IR(KBr)cm⁻¹ : 3406,2929,1676,1589

¹ H-NMR(CDCl₃)δ: 0.05(6 H,s),0.86(9 H,s),1.44(9 H,s),1.95-2.20(2H,m),3.20(1 H,m),3.35-3.55.(3 H,m),4.20(1 H,m), 4.35(1 H,t,J=3.0Hz),4.71(2 H,d,J=5.4 Hz),5.40(2 H,s), 7.45-7.70(2 H,m),8.01(1 H,s)

(Step 3)

To a solution of the compound (910 mg, 1.71 mmol) obtained in Step 2 inTHF (40 ml), triphenylphosphine (538 mg, 2.05 mmol) and phthalimide (302mg, 2.05 mol) were added. The resulting reaction solution was stirred atroom temperature in a nitrogen stream for 1 hour and then diethylazodicarboxylate was added dropwise to this reaction solution. Then thereaction solution was stirred at room temperature for 1 hour,concentrated in vacuo, and subjected to silica gel column chromatography(Wakogel™ C-300 ethyl acetate-heptane 1:3→1:2) to give a crude productcontaining(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-phthalimidomethyl-2-sulfamoyl)phenylthiomethylpyrrolidine.

To a solution of the crude product in ethanol (15 ml), hydrazine hydrate(592 mg, 11.8 mmol) was added. This solution was refluxed under heatingfor 4 hours and then poured into a liquid mixture of ethyl acetate with8% aqueous ammonia. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, andconcentrated in vacuo to give a crude powder. The crude powder isdissolved in a solvent mixture of dioxane (30 ml) with water (30 ml). Tothe resulting solution,4,6-dimethyl-2-(p-nitrobenzyloxycarbonylthio)pyrimidine (655 mg, 2.05mmol) was added while the solution was maintained at pH 8 by usingsaturated aqueous sodium hydrogencarbonate. Then, the solution wasstirred at room temperature overnight. After completion of the reaction,ethyl acetate was added to the reaction solution. The reaction solutionwas washed successively with 10% aqueous citric acid, saturated aqueoussodium hydrogencarbonate and saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, and concentrated in vacuo. Theresulting residue was subjected to silica gel column chromatography(Wakogel™ C-300 chloroform-methanol 100:2) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-p-nitrobenzyloxycarbonylaminomethyl-2-sulfamoyl)phenylthiomethylpyrrolidine(690 mg, yield: 57.3%) as a pale yellow foamy powder.

IR(KBr)cm⁻¹ : 3369,2933,1707,1524

¹ H-NMR(CDCl₃)δ: 0.05(6 H,s),0.85(9 H,s),1.43(9 H,s),1.90-2.10(2H,m),3.15(1 H,m),3.30-3.55(3 H,m),4.20(1 H,m), 4.30-4.45(3 H,m),5.22(2H,s),5.40(2 H,s),7.40-7.55(3 H,m),7.65(1 H,m),7.95(1 H,s),8.22(2H,d,J=8.5 Hz)

(Step 4)

To the compound (690 mg, 0.98 mmol) obtained in Step 3, 1.75NHCl-methanol solution (6 ml) was added under cooling with ice and thenresulting solution was stirred at room temperature overnight. Aftercompletion of the reaction, the reaction solution was concentrated invacuo to give a crude powder. This crude powder was dissolved in aliquid mixture of dioxane (10 ml) with water (10 ml). To the resultingsolution, 4,6-dimethyl-2-(p-nitrobenzyloxycarbonylthio)pyrimidine (375mg, 1.17 mmol) was added while the solution was maintained at pH 8 byusing saturated aqueous sodium hydrogencarbonate. Then, the reactionsolution was stirred at room temperature overnight. After completion ofthe reaction, ethyl acetate was added to the reaction solution. Theorganic layer was washed successively with 10% aqueous citric acid,saturated aqueous sodium hydrogencarbonate and saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, and then concentratedin vacuo. The resulting residue was subjected to silica gel columnchromatography (Wakogel™ C-300 chloroform-methanol 100:3) to give(2S,4R)-4-hydroxy-N-t-nitrobenzyloxycarbonyl-2-(4-p-nitrobenzyloxycarbonylaminomethyl)-2-sulfamoyl)phenylthiomethylpyrrolidine(480 mg, yield: 41.6%) as a colorless foamy powder.

IR(KBr)cm⁻¹ : 3390,1697,1520

¹ H-NMR(CDCl₃)δ: 1.90-2.10(2 H,m),3.05(1 H,m),3.40-3.80(3 H,m),4.05(1H,m),4.25-4.45(3 H,m),5.22(4 H,s), 6.07(2 H,s),6.30(1 H,s),7.35-7.60(5H,m), 7.72(1 H,d,J=9.0 Hz),7.97(1 H,d,J=2.0 Hz), 8.21(4 H,d,J=7.5 Hz)

(Step 5)

Diethyl azodicarboxylate was added to a solution of triphenylphosphine(97.8 mg, 0.37 mmol) in THF (5 ml) in a nitrogen stream under coolingwith ice and the resulting reaction solution was stirred at the sametemperature for 30 minutes. To this solution, a solution of the compound(210 mg, 0.31 mmol) obtained in Step 4 and thioacetic acid (0.027 ml,0.37 mmol) in THF (5 ml) was added dropwise and the resulting reactionsolution was stirred for 1 hour. After completion of the reaction, thereaction solution was concentrated in vacuo and subjected to silica gelcolumn chromatography (Wakogel™ C-300 ethyl acetate-heptane 1:2→2:1) togive (2S,4S)-4-acetylthio-2-(4-p-nitrobenzyloxycarbonylaminomethyl-2-sulfamoyl)phenylthiomethyl!-1-p-nitrobenzyloxycarbonylpyrrolidine(140 mg, yield: 61.4%) as a yellow oily substance.

IR(KBr)cm⁻¹ : 3340,1697,1518

¹ H-NMR(CDCl₃)δ: 2.05(1 H,m),2.35(3 H,s),2.60(2 H,m), 3.15(1 H,m),3.35(1H,m),3.70(1 H,m),3.90(1 H,m), 4.05(1 H,m),4.50(1 H,d,J=6.0 Hz),5.22(4H,s),5.30(2 H,s), 7.40-7.80(6 H,m),7.95(1 H,s),8.20(4 H,d,J=8-5 Hz)

In the following Reference Examples 6 to 94, the physicochemical data ofcompounds used in Examples as thiols or thiol precursors are shown.

Reference Example 6 ##STR210##

¹ H-NMR(CDCl₃)δ: 1.90-2.10(2 H,m),2.20-2.38(6 H,m),2.68-2.89(3H,m),3.78-4.00(1 H,m),4.01-4.23(2 H,m), 5.15(2 H,s),6.90-7.53(9H,m),8.10-8.28(2 H,m)

Reference Example 7 ##STR211##

IR(KBr)cm⁻¹ : 3245,1695,1531,1255

¹ H-NMR(CDCl₃)δ: 2.35(3 H,s),3.01-4.00(4 H,m),4.10-4.31(4 H,m),5.18(2H,s),7.10-7.85(12 H,m),8.13-8.25(2 H,m)

Reference Example 8 ##STR212##

¹ H-NMR(CDCl₃)δ: 1.90-2.10(1 H,m),2.34(3 H,s),2.43-2.69(1H,m),2.80-3.55(3 H,m),3.78-4.20(3 H,m),5.08-5.25(2 H,m),5.25-5.34(2H,m),6.62-6.75(1 H,m),7.17-7.63(8 H,m),8.12-8.30(4 H,m)

Reference Example 9 ##STR213##

¹ H-NMR(CDCl₃)δ: 2.04(2 H,s),2.85-3.00(4 H,m),3.12-3.35(2H,m),3.73-3.91(1 H,m),4.46(2 H,d,J=5.8 Hz),4.95-5.10(2 H,m),5.24(2H,s),7.13-7.57(25 H,m),7.65-7.90(3 H,m),8.05-8.25(4 H,m)

Reference Example 10 ##STR214##

¹ H-NMR(CDCl₃)δ: 1.92-2.08(1 H,m),2.34(3 H,d,J=2.0 Hz),2.85-3.53(3H,m),3.60-4.20(41 H,m),5.13.(2 H,s),5.28(2 H,s), 6.65-6.80(1H,m),7.15-7.60(9 H,m),8.10-8.30(4 H,m)

Reference Example 11 ##STR215##

IR(KBr)cm⁻¹ : 3425,1695,1519,1344,1162,759

¹ H-NMR(CDCl₃)δ: 1.85-2.06(1 H,m),3.49(3 H,s),2.90-3.60(4H,m),3.80-3.95(3 H,m),5.10-5.25(2 H,m),6.47-6.63(1 H,m),6.85-7.04(2H,m),7.10-7.32(2 H,m),7.40-7.59(5 H,m),7.70-7.90(2 H,m),8.15-8.26(2 H,m)

Reference Example 12 ##STR216##

¹ H-NMR(CDCl₃)δ: 2.05-2.11(2 H,m),2.51-2.70(2 H,m),2.88-2.95(4H,m),3.14-3.33(2 H,m),3.45-3.68(2 H,m),3.74-3.93(1 H,m),4.95-5.25(4H,m),7.15-7.65(24 H,m),7.72-7.90(4 H,m)

Reference Example 13 ##STR217##

¹ H-NMR(CDCl₃)δ: 1.55-1.95(2 H,m),2.01-2.15(1 H,m),2.65-3.90(7H,m),4.91-5.34(4 H,m),6.17-6.30(1 H,m),7.10-7.61(28 H,m),8.05-8.28(4H,m)

Reference Example 14 ##STR218## Starting material for diastereomer A

¹ H-NMR(CDCl₃)δ: 1.67-2.05(2 H,m),2.25-2.40(3 H,m),2.45-2.71(1H,m),2.90-4.35(9 H,m),4.91-5.25(4 H,m),7.05-7.55(5 H,m),8.05-8.26(4 H,m)

Starting material for diastereomer B

¹ H-NMR(CDCl₃)δ: 1.71-2.12(2 H,m),2.20-2.48(3 H,m),3.01-4.30(10H,m),5.02-5.25(4 H,m),7.05-7.55(5 H,m),8.06-8.28(4 H,m)

Reference Example 15 ##STR219##

¹ H-NMR(CDCl₃)δ: 1.56(1 H,s),2.50-2.95(4 H,m),3.67-3.86(3 H,m),4.53(2H,d,J=5.5 Hz),4.92-5.10(2 H,m),5.15-5.25(4 H,m),7.02-7.90(26H,m),8.12-8.25(4 H,m)

Reference Example 16 ##STR220##

¹ H-NMR(DMSO-d₆)δ: 1.80-1.95(1 H,m),2.33(3 H,d,J=1.2 Hz),3.29-3.38(4H,m),3.80-4.12(3 H,m),5.10-5.29(2 H,m),7.25-7.96(11 H,m),8.18(2H,d,J=7.9 Hz),10.22(1 H,s)

Reference Example 17 ##STR221## Starting material for diastereomer A

¹ H-NMR(CDCl₃)δ: 1.57(2 H,s),1.80-2.10(6 H,m),2.30-2.45(4H,m),3.70-3.87(1 H,m),3.99-4.40(4 H,m),4.68-4.99(2 H,m),7.10-7.40(7H,m),8.10-8.17(2 H,m)

Starting material for diastereomer B

¹ H-NMR(CDCl₃)δ: 1.60(2 H,s),1.85-2.10(6 H,m),2.33-2.47(4H,m),3.67-3.85(1 H,m),4.01-4.43(4 H,m),4.70-5.02(2 H,m),7.12-7.43(7H,m),8.12-8.20(2 H,m)

Reference Example 18 ##STR222##

IR(KBr)cm⁻¹ : 1705,1600,1520,1440,1400,1345,1105

¹ H-NMR(CDCl₃)δ: 2.65-3.01(4 H,m),3.70-3.90(1 H,m),4.05-4.21(2H,m),4.95-5.18(4 H,m),5.18-5.28(2 H,m),5.28-5.38(4 H,s),7.15-7.60(23H,m),7.75-7.85(2 H,m),8.15-8.29(4 H,m)

Reference Example 19 ##STR223##

IR(KBr)cm⁻¹ : 1705,1520,1345,1155,745

¹ H-NMR(CDCl₃)δ: 2.43-2.94(5 H,m),3.68-3.82(1 H,m),4.05-4.20(3H,m),4.93-5.39(8 H,m),7.12-7.68(24 H,m),8.05-8.24(5 H,m),8.67-8.74(1H,m)

Reference Example 20 ##STR224##

¹ H-NMR(CDCl₃)δ: 2.35(3 H,s),2.57-2.72(2 H,m),3.00-3.10(1H,m),3.27-3.43(1 H,m),3.68-3.76(1 H,m),3.85-3.95(1 H,m),4.08-4.28(2H,m),5.10-5.32(3 H,m),7.47-7.50(4 H,m),7.63(2 H,d,J=5.4 Hz),7.75(2 H,d,J=8.5 Hz),8.20 (2 H,d,J=8.5 Hz),8.52(2 H,d,J=6.4 Hz)

Reference Example 21 ##STR225##

¹ H-NMR(CDCl₃)δ: 1.83-2.01(2 H,m),2.30(3 H,s),2.82-3.03(2H,m),3.14-3.28(1 H,m),3.75-3.90(1 H,m),3.98-4.15(2 H,m),5.07-5.28(3H,m),7.19-7.64(7 H,m),7.99(3 H,br s),8.16(2 H,d,J=8.9 Hz),8.45-8.60(1H,m)

Reference Example 22 ##STR226##

¹ H-NMR(CDCl₃)δ: 1.80-1.95(1 H,m),2.32(3 H,s),2.40-2.80(2H,m),2.85-3.10(1 H,m),3.15-3.25(1 H,m), 3.72(2 H,s),3.80-4.15(3H,m),4.52-4.63(2 H,m),5.18-5.35(2 H,m),5.80-6.00(1 H,m),7.20-7.40(5 H,m)

Reference Example 23 ##STR227##

¹ H-NMR(CDCl₃)δ: 1.57(3 H,d,J=6.4 Hz),1.75-1.95(1 H,m), 2.32(3H,s),2.45-3.00(3 H,m),3.11-3.24(1 H,m),3.70-4.12(3 H,m),4.49-4.70(2H,m),5.16-5.40(3 H,m),5.72-6.17(1 H,m),7.20-7.42(5 H,m)

Reference Example 24 ##STR228##

¹ H-NMR(CDCl₃)δ: 1.89-2.05(1 H,m),2.33(3 H,s),2.40-2.65(1H,m),2.80-3.10(1 H,m),3.15-3.30(1 H,m),3.42-3.65(1 H,m),3.75-4.15(3H,m),4.12-4.48(2 H,m),5.16-5.37(2 H,m),5.80-6.12(1 H,m),7.19-7.42(4 H,m)

Reference Example 25 ##STR229##

IR(KBr)cm⁻¹ : 1700,1520,1345,1090

¹ H-NMR(CDCl₃)δ: 1.71-1.79(1 H,m),1.89-2.13(1 H,m),2.55-2.80(1H,m),3.10-3.68(4 H,m),3.92-4.03(1 H,m),4.10-4.28(1 H,m),4.47-4.60(2H,m),4.92-5.15(2 H,m),5.20-5.30(2 H,m),7.15-8.30(14 H,m)

Reference Example 26 ##STR230## Starting material for diastereomer A

IR(KBr)cm⁻¹ : 1695,1515,1345

¹ H-NMR(CDCl₃)δ: 2.00-2.20(1 H,m),2.34(3 H,s),3.10-3.35(1H,m),3.60-3.85(1 H,m),4.15-4.52(3 H,m),5.05-5.75(3 H,m),7.25-8.10(11H,m)

Starting material for diastereomer B

IR(KBr)cm⁻¹ : 1695,1520,1400,1345,1115

¹ H-NMR(CDCl₃)δ: 1.95-2.25(1 H,m),2.34(3 H,s),3.05-3.35(1H,m),3.60-4.78(4 H,m),5.10-5.95(3 H,m),6.90-7.10(1 H,m),7.35-8.05(10H,m)

Reference Example 27 ##STR231## Starting material for diastereomer A

¹ H-NMR(CDCl₃)δ: 1.70-1.95(2 H,m),2.15-2.27(1 H,m), 2.36(3H,s),2.91-3.04(1 H,m),3.39-3.58(2 H,m),3.65-3.94(2 H,m),4.08-4.22(1H,m),4.32-4.86(3 H,m),5.00-5.25(3 H,m),6.94-7.33(4 H,m),7.40-7.70(5H,m),7.70-7.90(1 H,m),8.05-8.28(4 H,m),8.35-8.50(1 H,m)

Starting material for diastereomer B

¹ H-NMR(CDCl₃)δ: 1.70-2.05(3 H,m),2.34(3 H,s),2.50-2.70(1H,m),3.34-3.84(4 H,m),3.95-4.35(2 H,m),4.55-5.28(5 H,m),6.95-7.10(1H,m),7.35-7.63(6 H,m),7.65-7.92(3 H,m),7.93-8.48(5 H,m)

Reference Example 28 ##STR232##

¹ H-NMR(CDCl₃)δ: 1.65-2.09(3 H,m),2.31(3 H,s),2.85-3.39(3H,m),3.59-3.85(1 H,m),3.92-4.42(4 H,m),4.52-4.63(1 H,m),5.07-5.35(3H,m),5.60-6.01(1 H,m),7.09-7.50(10 H,m)

Reference Example 29 ##STR233## Starting material for diastereomer A

IR(KBr)cm⁻¹ : 1700,1525,1405,1345,1115

¹ H-NMR(CDCl₃)δ: 1.49-2.10(6 H,m),2.33(3 H,s),2.51-2.72(1H,m),3.04-3.23(1 H,m),3.34-3.82(3 H,m),4.10-4.39(2 H,m),4.95-5.30(2H,m),5.62-5.85(1 H,m),7.05-7.19(1 H,m),7.35-7.58(5 H,m),7.60-7.85(3H,m),7.86-8.05(1 H,m),8.15-8.30(1 H,m)

Starting material for diastereomer B

IR(KBr)cm⁻¹ : 1700,1525,1420,1345,1115

¹ H-NMR(CDCl₃)δ: 1.52-1.71(1 H,m),1.75-2.20(6 H,m), 2.35(3H,s),3.01-3.19(1 H,m),3.45-4.05(4 H,m),4.10-4.45(3 H,m),4.60-4.72(1H,m),5.80-5.95(1 H,m),6.90-7.00(1 H,m),7.30-7.55(4 H,m),7.60-7.85(4H,m),7.90-8.05(2 H,m)

Reference Example 30 ##STR234## Starting material for diastereomer A

IR(KBr)cm⁻¹ : 1700,1525,1410,1340,1115

¹ H-NMR(CDCl₃)δ: 1.70-2.05(2 H,m),2.33(3 H,s),2.55-2.70(1 H,m),2.92(3H,s),3.05-3.52.(3 H,m),3.63-4.45(5 H,m),4.52-5.30(3 H,m),6.89-7.25(2H,m),7.35-8.00(8 H,m),8.15-8.30(1 H,m)

Starting material for diastereomer B

IR(KBr)cm⁻¹ : 1700,1520,1415,1340,1150,1115

¹ H-NMR(CDCl₃)δ: 1.65-2.25(4 H,m),2.36(3 H,s),2.93(3 H,s), 3.02-3.55(3H,m),3.65-4.05(2 H,m),4.06-4.48(2 H,m),4.55-5.01(2 H,m),6.89-6.98(1H,d,J=8.7 Hz),7.15-7.55(3 H,m),7.61-7.78(3 H,m),7.82-8.05(4 H,m)

Reference Example 31 ##STR235##

IR(KBr)cm⁻¹ : 3452,1743,1699,1404,1352,1230,1113,1045

¹ H-NMR(CDCl₃)δ: 1.90-2.05(1 H,m),2.17(3 H,s),2.34(3 H,s), 2.50-2.60(1H,m),2.90-4.20(6 H,m),4.50-4.60(2 H,m),5.15-5.35(4 H,m),5.80-6.00(1H,m),7.25-7.50(3 H,m)

Reference Example 32 ##STR236##

IR(KBr)cm⁻¹ : 3435,1691,1406,1354,1115,606

¹ H-NMR(CDCl₃)δ: 1.90-2.10(1 H,m),2.34(3 H,s),2.60-2.75(1H,m),3.20-4.15(4 H,m),4.50-4.65(2 H,m),5.20-5.35(2 H,m),5.75-6.00(2H,m),6.50-6.65(1 H,m),7.30-7.70(3 H,m)

Reference Example 33 ##STR237##

IR(KBr)cm⁻¹ : 3452,1695,1647,1601,1531,1408,1346,1113

¹ H-NMR(CDCl₃)δ: 1.95-2.05(1 H,m),2.35(3 H,s),2.50-2.65(1 H,m),3.00(3H,s),3.05-4.20(6 H,m),5.15-5.30(2 H,m),6.00-6.10(1 H,br s),7.40-8.25(8H,m)

Reference Example 34 ##STR238##

IR(KBr)cm⁻¹ : 3454,1693,1593,1531,1518,1408,1346

¹ H-NMR(CDCl₃)δ: 1.90-2.10(1 H,m),2.35(1 H,s),2.50-2.60(1H,m),2.80-3.20(8 H,m),3.20-4.20(4 H,m),5.15-5.30(2 H,m),7.20-8.30(8 H,m)

Reference Example 35 ##STR239##

IR(KBr)cm⁻¹ : 3454,1693,1601,1518,1408,1346,1113

¹ H-NMR(CDCl₃)δ: 1.90-2.10(1 H,m),2.35(3 H,s),2.50-2.65(1H,m),3.20-3.70(4 H,m),3.80-4.20(2 H,m),5.15-5.20(2 H,m),5.30-5.40(2H,br),7.10-8.30(8 H,m)

Reference Example 36 ##STR240##

IR(KBr)cm⁻¹ : 3429,1676,1554,1408,1348,1120,768,608

¹ H-NMR(CDCl₃)δ: 1.90-2.10(1 H,m),2.37(3 H,s),2.60-3.00(3H,m),3.30-3.50(1 H,m),3.70-4.20(4 H,m),4.55-4.70(2 H,m),5.20-5.40(2H,m),5.50-5.60(1 H,br),5.80-6.00(1 H,m),7.40-8.30(3 H,m)

Reference Example 37 ##STR241##

IR(KBr)cm⁻¹ : 1701,1439,1406,1321,1254,1146,1103,989

¹ H-NMR(CDCl₃)δ: 1.60-1.80(1 H,m),2.15-2.25(1 H,m),2.70-3.00(2H,m),3.50-3.80(7 H,m),4.40-4.60(4 H,m),5.15-5.50(5 H,m),5.80-6.00(2H,m),6.05-6.25(1 H,br),7.20-7.55(19 H,m)

Reference Example 38 ##STR242##

IR(KBr)cm⁻¹ : 2950,2450,1701,1439,1410,1329,1178,1103,989, 704

¹ H-NMR(CDCl₃)δ: 1.70-1.85(1 H,m),2.0-2.20(1 H,m),2.70-3.00(5H,m),3.30-3.40(3 H,m),3.75-3.90(1 H,m),4.20-4.70(7 H,m),5.15-5.30(4H,m),5.50-5.60(1 H,m),5.70-5.90(3 H,m),7.20-7.50(19 H,m)

Reference Example 39 ##STR243##

¹ H-NMR(CDCl₃)δ: 2.32(3 H,s),4.42(2 H,br d),4.90-5.40(4 H,m),7.10-7.60(12 H,m),7.90-8.30(4 H,m)

Reference Example 40 ##STR244##

IR(KBr)cm⁻¹ : 3747,2925,1700,1519,1346,1247,1114,848,630

¹ H-NMR(CDCl₃)δ: 1.59(1 H,s),2.34(3 H,s),2.56(3 H,t),2.88-3.10(2H,m),3.31-3.34(3 H,m),3.49(1 H,s),3.60(1 H,s), 3.65(2 H,s),3.80-4.00(1H,m),5.18(4 H,d,J=4.7 Hz),7.23-7.52(8 H,m),8.19-8.23(4 H,d,J=8.7 Hz)

Reference Example 41 ##STR245##

IR(KBr)cm⁻¹ : 3500,2900,1695,1454,1430,1403

¹ H-NMR(CDCl₃)δ: 1.92-2.12(1 H,m),2.34(3 H,s),2.50-2.73(1H,m),2.86-3.06(1 H,m),3.23-3.38(1 H,m),3.49-4.25(4 H,m),4.52-4.67(2H,m),5.18-5.41(2 H,m),5.83-6.05(1 H,m),7.00-7.72(4 H,m)

Reference Example 42 ##STR246##

IR(KBr)cm⁻¹ : 3330,3075,2925,1695,1604,1519

¹ H-NMR(CDCl₃)δ: 1.95-2.20(1 H,m),2.34(3 H, s),2.46-2.73(1H,m),3.03-3.50(2 H,m),3.62-4.28(4 H,m),4.75-5.37(7 H,m),7.10-7.83(8H,m),7.92-8.10(2 H,m),8.14-8.31(3 H,m),8.37-8.53(1 H,m)

Reference Example 43 ##STR247##

¹ H-NMR(CDCl₃)δ: 1.80-1.90(1 H,m),2.70-2.90(2 H,m),3.30-3.50(3H,m),4.10-4.20(2 H,m),4.80-5.00(2 H,m),5.60-5.80(3 H,m),6.10-6.20(1 H,m)

Reference Example 44 ##STR248##

IR(KBr)cm⁻¹ : 3344,2877,1695,1525,1403,1349,1238,1110,861

¹ H-NMR(CDCl₃)δ: 1.90-2.10(1 H,m),2.34(3 H,s),2.80-4.20(5H,m),5.10-5.30(5 H,m),6.70-6.80(2 H,m),7.20-7.50(6 H,m),8.10-8.20(4 H,m)

Reference Example 45 ##STR249##

¹ H-NMR(CDCl₃)δ: 1.90-2.10(1 H,m),2.35(3 H,s),2.90-3.30(6H,m),3.50-4.20(5 H,m),5.16(2 H,s),5.19(2 H,s), 5.50-5.70(1H,br),7.00-7.60(8 H,m),8.20-8.30(4 H,m)

Reference Example 46 ##STR250## Starting material for Diastereomer A

¹ H-NMR(CDCl₃)δ: 2.36(3 H,s),3.45-3.60(2 H,m),3.70-4.00(3 H,m),4.30(1H,m),4.58(2 H,m),5.20-5.35(2 H,m), 5.91(1 H,m),7.26-7.35(3H,m),7.40-7.55(2 H,m)

Reference Example 47 ##STR251##

¹ H-NMR(CDCl₃)δ: 1.97(1 H,m),2.33(3 H, s),2.55(1 H,m), 2.97(1H,m),3.22(1 H,m),3.58(1 H,m),3.87(1 H,m), 4.04(2 H,m),4.45-4.75(8H,m),5.15-5.38(4 H,m),5.80-6.05(2 H,m),7.10-7.40(3 H,m)

Reference Example 48 ##STR252##

¹ H-NMR(CDCl₃)δ: 1.94(1 H,m),2.33(3 H,s),2.55(1 H,m), 2.80(1 H,m),3.27(1H,m),3.70(1 H,m),3.89(1 H,m), 4.02(2 H,m),4.30-4.60(10 H,m),5.15-5.35(6H,m),5.75-5.95(3 H,m),7.22(2 H,m),7.56(1 H,s)

Reference Example 49 ##STR253##

IR(KBr)cm⁻¹ : 2962,1704,1606,1523,1425,1402,1346,1199,1145,1106,1012,854,825,765,736,549

¹ H-NMR(CDCl₃)δ: 1.56(9 H,s),1.71(1 H,d,J=5.5 Hz),1.90(1 H,m), 2.62(1H,m),3.10-3.20(3 H,m),3.55(1 H,m),4.00-4.20(2 H,m),5.15(2 H,s),7.24(2H,d,J=5.5 Hz),7.33(2 H,d,J=5.5 Hz),7.49(2 H,d,J=8.3 Hz),8.21(2 H,d,J=8.3Hz)

Reference Example 50 ##STR254##

IR(KBr)cm⁻¹ : 1700,1606,1591,1571,1519,1454,1427,1402,1346,1257,1199,1147,1106,1022,894,852,804,767, 736,599

¹ H-NMR(CDCl₃)δ: 1.77(1H,d,J=5.3 Hz),1.92(1 H,m),2.69(1 H,m),3.10-3.30(3 H,m),3.63(1 H,dd,J=2.3 & 13.4 Hz),4.00-4.20(2 H,m),5.22(2H,s),6.74(1 H,m),7.30-7.50(4 H,m),8.22(2 H,d,J=8.5 Hz)

Reference Example 51 ##STR255##

IR(KBr)cm⁻¹ : 2921,1695,1477,1403,1322,1197,1147,1106,987,933,810,769,495

¹ H-NMR(CDCl₃)δ: 1.69(1 H,m),1.88(1 H,m),2.46(3 H,s), 2.55(1H,m),3.00-3.30(3 H,m),3.51(1 H,m),3.90-4.10(2 H,m),4.52(2 H,m),5.23(2H,m),5.87(1 H,m),7.20-7.30(4 H,m)

Reference Example 52 ##STR256##

IR(KBr)cm⁻¹ : 3448,2929,1691,1479,1421,1365,1197,1106,1047, 1010,811,769

¹ H-NMR(CDCl₃)δ: 1.71(1 H,m),1.89(1 H,m),2.57(1 H,m),3.00-3.30(6H,m),3.73(2 H,t,J=5.9 Hz),4.05(2 H,m),4.53(2 H,m), 5.20-5.30(2H,m),5.91(1 H,m),7.31(4 H,s)

Reference Example 53 ##STR257##

IR(KBr)cm⁻¹ : 3380,3183,1693,1631,1407,1195,1108,808

¹ H-NMR(CDCl₃)δ: 1.71(1 H,d,J=6.3 Hz),1.85(1 H,m),2.59(1 H,m),3.00-3.30(3 H,m),3.58(2 H,s),3.60(1 H,m),4.05(2 H,m), 4.53(2 H,m),5.25(2H,m),5.45(1 H,m),5.90(1 H,m), 6.61(1 H,m),7.20-7.40(4 H,m)

Reference Example 54 ##STR258##

IR(KBr)cm⁻¹ : 1700,1519,1402,1348,1253,1147,1095,852,763,

¹ H-NMR(CDCl₃)δ: 1.78(1 H,d,J=6.0 Hz),1.85(1 H,m),2.65(1 H,m),3.10-3.40(5 H,m),3.60-3.80(3 H,m),4.00-4.20(2 H,m), 5.18(4 H,s),5.59(1H,m),7.50(4 H,d,J=8.0 Hz), 7.61(2 H,d,J=8.4 Hz),7.77(2 H,d,J=8.4 Hz),8.22(2 H,d,J=8.0 Hz)

Reference Example 55 ##STR259##

IR(KBr)cm⁻¹ : 1700,1581,1519,1400,1348,1305,1199,1149,1095

¹ H-NMR(CDCl₃)δ: 1.77(1 H,d,J=6.3 Hz),1.87(1 H,m),2.66(1 H,m), 3.03(3H,s),3.20-3.40(3 H,m),3.76(1 H,dd,J=2.8 & 13.7 Hz), 4.00-4.20(2H,m),5.15 and 5.23(each 1 H,ABq,J=12.0 Hz), 7.51(2 H,d,J=8.7 Hz),7.58(2H,d,J=8.5 Hz), 7.82(2 H,d,J=8.5 Hz),8.23(2 H,d,J=8.7 Hz)

Reference Example 56 ##STR260##

¹ H-NMR(CDCl₃)δ: 1.71-1.95(2 H,m),2.55-2.69(1H,m),3.18-4.13(5H,m),4.86(1 H,s),5.18(2 H,s),5.29-5.33(4 H,m), 7.20-8.28(12 H,m)

Reference Example 57 ##STR261##

¹ H-NMR(CDCl₃)δ: 1.84-1.96(2 H,m),2.33(3 H,s),2.53-4.13(16H,m),5.20-5.27(4 H,m),7.37-8.28(12 H,m)

Reference Example 58 ##STR262##

¹ H-NMR(CDCl₃)δ: 1.86-2.19(2 H,m),2.35(3 H,s),2.42-3.30(5H,m),3.67-3.95(3 H,m),4.36-4.40(2 H,m),5.20-5.22(4 H,m),7.21-8.26(12H,m)

Reference Example 59 ##STR263##

¹ H-NMR(CDCl₃)δ: 1.80-1.99(2 H,m),2.31(3 H,s),2.49-3.28(5H,m),3.70-3.95(3 H,m),5.18(2 H,s),5.42(2 H,s), 7.39-7.62(6H,m),7.97-8.28(6 H,m).

Reference Example 60 ##STR264##

IR(KBr)cm⁻¹ : 3429,2368,1699,1522,1346

¹ H-NMR(CDCl₃)δ: 2.00(1 H,m),2.36(3 H,s),2.65(1 H,m), 3.18(1 H,m),3.35(1H,dd,J=7.0 & 10.0 Hz),3.49(2 H,m), 3.59(2 H,m),3.75(1 H,d,J=12.0Hz),3.94(1 H,t,J=8.0 Hz), 4.05-4.25(2 H,m),5.20(4 H,d,J=5.2 Hz),5.43(2H,m), 5.52(1 H,m),7.20(1 H,s),7.45(2 H,d,J=8.9 Hz), 7.50(2 H,d,J=8.6Hz),7.75(1 H,d,J=9.0 Hz), 7.88(1 H,d,J=9.0 Hz),8.09(2 H,d,J=8.9 Hz),8.21(2 H,d,J=8.6 Hz),8.31(1 H,s)

Reference Example 61 ##STR265##

IR(KBr)cm⁻¹ : 3697,1703,1524,1348,1093

¹ H-NMR(CDCl₃)δ: 2.05(1 H,m),2.36(3 H, s),2.57(3 H,d,J=5.3 Hz), 3.15(1H,m),3.35(1 H,m),3.50(2 H,m),3.62(2 H,m), 3.78(1 H,m),3.95(1 H,t,J=7.0Hz),4.05-4.25(2 H,m), 5.23(4 H,s),5.45(1 H,br s),7.12(1 H,br s), 7.49(4H,d,J=9.3 Hz),7.85(1 H,d,J=9.3 Hz), 7.98(1 H,d,J=9.3 Hz),8.10-8.25(4H,m),8.30(1 H,s)

Reference Example 62 ##STR266##

IR(KBr)cm⁻¹ : 3388,1697,1578,1522,1346

¹ H-NMR(CDCl₃)δ: 1.97(1 H,m),2.35(3 H,s),2.60(1 H,m),3.02-3.15(3H,m),3.25-3.40(3 H,m),3.73(1 H,dd,J=2.7 & 13.3 Hz), 3.91(1H,m),4.05-4.20(2 H,m),4.92(1 H,m),5.19(4 H,s), 5.24(1 H,m),7.45-7.55(6H,m),7.73(1 H,d,J=8.5 Hz), 8.22(2 H,d,J=8.8 Hz),8.23(2 H,d,J=8.8 Hz)

Reference Example 63 ##STR267##

¹ H-NMR(CDCl₃)δ: 2.00(1 H,m),2.35(3 H,s),2.45-2.70(3 H,m), 3.05-3.40(3H,m),3.70(2 H,s),3.92(1 H,m),4.03-4.25(2 H,m),5.19(4 H,d,J=8.3Hz),5.53(2 H,s),7.47(1 H,d,J=9.0 Hz),7.52(4 H,d,J=8.9 Hz),7.75(1H,d,J=9.0 Hz),7.90(1 H, s),8.15-8.25(4 H,m)

Reference Example 64 ##STR268##

IR(KBr)cm⁻¹ : 1772,1747,1699,1686,1650,1574,1558

¹ H-NMR(CDCl₃)δ: 1.70(1 H,m),1.85(1 H,m),2.60(1 H,m),2.90-3.50(4H,m),3.90-4.15(2 H,m),5.15-5.50(4 H,m),5.78-6.15(2 H,m),6.76(1 H,d,J=7.4Hz),7.22(1 H,dd,J=1.6 & 7.4 Hz),7.47(1 H,d,J=1.6 Hz)

Reference Example 65 ##STR269##

IR(KBr)cm⁻¹ : 1695,1643,1533,1408,1092

¹ H-NMR(CDCl₃)δ: 1.85(1 H,m),2.60(1 H,m),3.00-3.35(3 H,m), 3.45(2H,m),3.55(2 H,m),3.65(1 H,m),3.95-4.20(2 H,m),4.50-4.65(4H,m),5.15-5.40(4 H,m),5.80-6.05(2 H,m),7.45(2 H,m),7.70(2 H,m)

Reference Example 66 ##STR270##

IR(KBr)cm⁻¹ : 1695,1593,1549,1531,1408,1311,1142

¹ H-NMR(CDCl₃)δ: 2.00(1 H,m),2.65(1 H,m),3.04(1 H,m), 3.22(3 H,s),3.33(1H,m),3.46(2 H,m),3.60(2 H,m),3.80-4.00(2 H,m),4.03-4.20(2H,m),4.53-4.75(4 H,m),5.15-5.45(4 H,m),5.80-6.10(2 H,m),7.65(1 H,d,J=8.2Hz), 8.05(1 H,d,J=8.2 Hz),8.40(1 H,br s)

Reference Example 67 ##STR271##

IR(KBr)cm⁻¹ : 1684,1589,1520,1473,1408,1377,1117

¹ H-NMR(CDCl₃)δ: 1.90(1 H,m),2.18(3 H,s),2.65(1 H,m),3.00-3.85(4H,m),3.90-4.20(2 H,m),4.45-4.60(2 H,m),5-15-5.35(2 H,m),5.80-6.00(1H,m),7.20-7.40(2 H,m),7.60(1 H,m)

Reference Example 68 ##STR272##

IR(KBr)cm⁻¹ : 1697,1522,1346,1123

¹ H-NMR(CDCl₃)δ: 1.95(1 H,m),2.60(1 H,m),2.70-3.45(3 H,m), 3.65-4.20(3H,m),4.65(1 H,m),4.80(1 H,m),5.05-5.25(4 H,m),7.30-7.70(6H,m),8.10-8.30(5 H,m)

Reference Example 69 ##STR273##

¹ H-NMR(CDCl₃)δ: 1.73(1 H,d,J=6.3 Hz),1.80-1.90(1 H,m),2.60-2.70(1H,m),3.00-3.70(8 H,m),3.90-4.10(2 H,m), 4.55(4 H,d,J=5.4 Hz),5.15(1H,br),5.20-5.30(4 H,m), 5.77(1 H,br),5.84-5.96(2 H,m),7.03(1H,br),7.30-7.70(3 H,m)

Reference Example 70 ##STR274##

¹ H-NMR(CDCl₃)δ: 2.00(1 H,m),2.34(3 H,s),2.57(1 H,m),2.75-3.60(3H,m),3.88(1 H,m),4.10(2 H,m),4.37(2 H,m), 5.15(2 H,s),5.20(2H,s),5.10-5.30(1 H,m),6.70-7.00(4 H,m),7.15-7.60(8 H,m),8.10-8-30(4 H,m)

Reference Example 71 ##STR275##

¹ H-NMR(CDCl₃)δ: 2.05(1 H,m),2.35(3 H,s),2.60(1 H,m),2.90-3.20(3H,m),3.20-3.70(4 H,m),3.90(1 H,m),4-10(2 H,m), 5.05-5.25(4H,m),5.90-6.15(2 H,br),6.35-6.70(1 H,br),7.20-7.80(11 H,m),8.15(4 H,m)

Reference Example 72 ##STR276##

¹ H-NMR(CDCl₃)δ: 1.70-2.01(1 H,m),2-38-2.70(1 H,m),3.75-4.00(9H,m),5.15-5.31(2 H,m),6.48-6.61(2 H,m),7.10-7.30(1 H,m),7.41-7.55(2H,m),8.10-8.30(2 H,m)

Reference Example 73 ##STR277##

¹ H-NMR(CDCl₃)δ: 2.01(1 H,m),2-30(3 H,s),2-53(1 H,m), 2.83(1 H,m),2.91(1H,m),3.62(2 H,m),3.71(3 H,s), 3.90(2 H,m),5.10(2 H,m),7.40(8 H,m),8.19(4H,m)

Reference Example 74 ##STR278##

¹ H-NMR(CDCl₃)δ: 2.02(1 H,m),2.16(6 H,s),2.34(3 H,s), 2.59(1 H,m),3.03(1H,m),3.26(1 H,m),3.34(2 H,s), 3.67(1 H,m),3.86(1 H,m),4.12(2 H,m),4.51(2H,m), 5.25(2 H,m),5.90(1 H,m),7.19(1 H,s),7.36(6 H,m), 7.58(1 H,s)

Reference Example 75 ##STR279##

¹ H-NMR(CDCl₃)δ: 1.96(2 H,m),2.03(3 H,s),2.74(2 H,m), 3.06(1 H,m),3.69(2H,m),3.96(1 H,m),4.62(2 H,m), 5.10(2 H,s),5.23(2 H,s),5.84(1H,s),7.40(12 H,m), 8.19(4 H,m)

Reference EXAMPLE 76 ##STR280##

¹ H-NMR(CDCl₃)δ: 1.39(1 H,m),2.02(1 H,m),2.30(3 H,s), 2.50(1 H,m),2.82(1H,m),2.96(1 H,m),3.66(2 H,m), 3.91(1 H,m),5.08(2 H,s),5.46(2H,s),7.46(12 H,m), 8.21(4 H,m)

Reference Example 77 ##STR281##

¹ H-NMR(CDCl₃)δ: 2.01(1 H,m),2.36(3 H,s),2.58(1 H,m), 2.74(3 H,s),3.03(1H,m),3.29(1 H,m),3.56(1 H,m), 3.89(1 H,m),4.12(2 H,m),4.46(2 H,m),5.19(4H,m), 7.42(12 H,m),8.19(4 H,m)

Reference Example 78 ##STR282##

¹ H-NMR(CDCl₃)δ: 1.86(1 H,m),2.01(1 H,m),2.86(1 H,m), 3.47(3 H,m),3.76(2H,m),4.16(3 H,m),4.34(1 H,m), 5.19(4 H,s),5.52(1 H,s),5.91(1H,s),7.40(12 H,m), 8.16(4 H,m)

Reference Example 79 ##STR283##

IR(KBr)cm⁻¹ : 3650,3080,2940,2870,1700,1510,1360,1090,960, 850,740

¹ H-NMR(CDCl₃)δ: 1.68(1 H,m),1.83(1 H,m),2.25(1 H,m), 2.33(3 H,s),2.58(1H,m),2.70-3.00(2 H,m),3.19(1 H,m),3.88(1 H,m),4.00-4.15(2H,m),5.10-5.30(2 H,m),7.15-7.40(5 H,m),7.40-7.60(2 H,m),8.10-8.30(2 H,m)

Reference Example 80 ##STR284##

IR(KBr)cm⁻¹ : 3750,2940,1770,1700,1520,1350,1260,1180,1090, 850,740

¹ H-NMR(CDCl₃)δ: 1.75(1 H,m),2.26(1 H,m),2.70-3.10(3 H,m), 3.26,3.45(1H,m),3.86(1 H,m),5.00-5.10(3 H,m), 5.30(4 H,s),7.10-7.30(13 H,m),7.37(1H,d,J=8.0 Hz), 7.43(6 H,d,J=7.0 Hz),7.52(4 H,d,J=8.0 Hz),8.10-8-30(6H,m)

Reference Example 81 ##STR285##

IR(KBr)cm⁻¹ : 3650,3080,2940,1710,1510,1360,1290,1090,960, 830,740

¹ H-NMR(CDCl₃)δ: 1.95-2.10(1 H,m),2.34(3 H,s),2.40-2.70(1H,m),2.88,3.08(1 H,m),3.20-3.50(2 H,m),3.75(3 H, s),3.87(1H,m),3.95-4.15(2 H,m),5.00-5.20(2 H,m),6.70-6.90(2 H,m),7.25-7.50(4H,m),8.15-8.30(2 H,m)

Reference Example 82 ##STR286##

IR(KBr)cm³¹ 1 : 3750,2950,1690,1520,1340,1290,1100,960,840, 740

¹ H-NMR(CDCl₃)δ: 2.09(1 H,m),2.33(3 H,s),2.40(1 H,m), 2.92,3.07(1H,m),3.30-3.50(2 H,m),3.87(1 H,m),4.00-4.25(2 H,m),5.10-5.25(2H,m),1.10-7.35(4 H,m),7.40-7.50(3 H,m),8.15-8.25(2 H,m)

Reference Example 83 ##STR287##

IR(KBr)cm⁻¹ : 3650,3080,2940,1710,1510,1360,1290,1090,960, 830,730

¹ H-NMR(CDCl₃)δ: 2.09(1 H,m),2.33(3 H,s),2.41(1 H,m), 2.92,3.07(1H,m),3.30-3.50(2 H,m),3.85(1 H,m),4.00-4.25(2 H,m),5.10-5.25(2H,m),7.10-7.35(4 H,m),7.35-7.50(3 H,m),8.15-8.25(2 H,m)

Reference Example 84 ##STR288##

IR(KBr)cm⁻¹ : 3650,3080,2940,1700,1510,1360,1290,1090,950, 850,740

¹ H-NMR(CDCl₃)δ: 2.01(1 H,m),2.34(3 H,s),2.56(1 H,m), 2.98,3.10(1H,m),3.26(1 H,m),3.42,3.58(1 H,m), 3.88(1 H,m),4.00-4.20(2 H,m),5.14(2H,s),7.10-7.35(4 H,m),7.35-7.50(3 H,m),8.15-8.25(2 H,m)

Reference Example 85 ##STR289##

IR(KBr)cm⁻¹ : 3750,2930,1700,1520,1440,1400,1340,1150,1090, 750,700

¹ H-NMR(CDCl₃)δ: 1.69(1 H,m),2.09(1 H,m),2.45-2.60(2 H,m), 2.60-2.90(3H,m),3.00(3 H,s),3.75(1 H,d,J=14.0 Hz), 3.91(1 H,m),4.49(1 H,d,J=14.0Hz),5.04(2 H,s),7.10-7.45(17 H,m),7.45-7.65(3 H,m),7.80-7.90(2H,m),8.10-8.25(3 H,m),8.62(1 H,s)

Reference Example 86 ##STR290##

IR(KBr)cm⁻¹ : 3750,2940,1700,1520,1400,1350,1200,1100,960, 850,740

¹ H-NMR(CDCl₃)δ: 2.08(1 H,m),2.33(3 H,m),2.50-2.75(1 H,m), 3.00-3.40(2H,m),3.15-3.50(1 H,m),3.88(1 H,m),4.00-4.30(2 H,m),4.90-5.20(2H,m),7.25-7.50(5 H,m), 7.64(1 H,m),7.70-7.95(3 H,m),8.00,8.15(2H,d,J=8.0 Hz)

Reference Example 87 ##STR291##

¹ H-NMR(CDCl₃)δ: 1.74(1 H,m),2.30(3 H,s),2.46(1 H,m),3.20-3.70(4H,m),3.90-4.20(2 H,m),4.60(2 H,m),5.15-5.40(2 H,m),5.90(1H,m),7.20-7.50(5 H,m)

Reference Example 88 ##STR292##

¹ H-NMR(CDCl₃)δ: 1.76(1 H,m),2.04(3 H,s),2.28(1 H,m),2.70-3.10(3H,m),3.60(1 H,m),3.72(1H,m),4.40(3 H,m), 4.60(2 H,m),4.86(2H,m),5.10-5.50(6 H,m),5.60-6.15(3 H,m),7.10-7.40(10 H,m),7.40-7.70(10H,m), 8.22(2 H,m)

Reference Example 89 ##STR293##

IR(KBr)cm⁻ : 3400,3330,3060,2940,1700,1520,1440,1402,1350,1250,1110,1050,850,740

¹ H-NMR(CDCl₃)δ: 1.23(1 H,m),2.24(1 H,m),2.6-3.0(4 H,m),3.65-3.9(3H,m),4.0-4.2(2 H,m),4.4-4.7(3 H,m),4.8-5.3(2 H,m),5.14(2 H,s),5.20(2H,s),5.7-6.1(2 H,m),7.1-7.6(23 H,m),7.7-8.1(3 H,m),8.08(4 H,d,J=8 Hz),8.16(2 H,d,J=8 Hz),8.53(1 H,m)

Reference Example 90 ##STR294##

IR(KBr)cm⁻¹ : 1706,1519,1346

¹ H-NMR(CDCl₃)δ: 1.68(1 H,m),2.25(1 H,m),2.60-3.95(4 H,m), 3.15(2H,m),3.60(2 H,m),3.70-4.00(2 H,m),4.50(2 H,m), 4.80-5.30(4H,m),5.60-5.80(2 H,m),7.10-7.50(21 H,m),7.65-7.85(4 H,m),7.95-8.23(4H,m)

Reference Example 91 ##STR295##

IR(KBr)cm⁻¹ : 1700,1521,1346

¹ H-NMR(CDCl₃)δ: 1.69(1 H,m),2.23(1 H,m),2.65-2.98(5 H,m), 3.75-3.95(5H,m),4.60(2 H,m),4.84(2 H,m),5.06(4 H,s), 5.22(2 H,s),7.15-7.55(23H,m),7.70-8.00(4 H,m),8.04-8.20(5 H,m)

Reference Example 92 ##STR296##

IR(KBr)cm⁻¹ : 1697,1519,1403,1344,1199,1105,746,702

¹ H-NMR(CDCl₃)δ: 1.75(1 H,m),2.18(1 H,m),2.55-2.95(3 H,m), 3.65-3.90(3H,m),4.78-5.12(6 H,m),7.00-7.50(17 H,m),7.55-7.95(6 H,m),8.20(2 H,m)

Reference Example 93 ##STR297##

IR(KBr)cm⁻¹ : 1695,1518,1404,1344,1200,1107,758,608

¹ H-NMR(CDCl₃)δ: 1.74(1 H,m),2.56(1 H,m),2.84(1 H,m), 3.07(1H,m),3.10-3.26(3 H,m),4.92-5.08(5 H,m), 5.16(2 H,s),7.47(4H,m),7.80-7.86(4 H,m),8.19(2 H,d,J=8.5 Hz)

Reference Example 94 ##STR298##

IR(KBr)cm⁻¹ : 1699,1519,1408,1346,1281,1184,1107,841, 746,706

¹ H-NMR(CDCl₃)δ: 1.74(1 H,m),2.20(1 H,m),2.54-3.00(3 H,m), 3.58-3.85(3H,m),4.80-5.15(6 H,m),7.10-7.55(17 H,m),7.60-7.70(6 H,m),8.08(2 H,m)

Reference Example 95

(2S,4S)-N-(p-Nitrobenzyloxycarbonyl)-2- 4-N-P-nitrobenzyloxycarbonyl)aminomethyl!anilinomethyl!-4-tritylthiopyrrolidine##STR299## (Step 1)

Dimethyl sulfoxide (1.06 ml, 14.9 mmol) was added to a solution ofoxalyl chloride (0.648 ml, 7.43 mmol) in methylene chloride (40 ml) at-78° C. in a nitrogen stream over 2 minutes. The resulting reactionsolution was stirred at the same temperature for 10 minutes. To thisreaction solution, a solution of(2S,4S)-2-hydroxymethyl-N-(p-nitrobenzyloxycarbonyl)-4-tritylthiopyrrolidine(2.47 g, 4.45 mmol) in methylene chloride (10 ml) was added dropwiseover 5 minutes. This reaction mixed solution was stirred for 10 minutesand then triethylamine (3.11 ml, 22.3 mmol) was added dropwise over 2minutes. This reaction solution was reverted to room temperature over 30minutes, brought together with saturated aqueous ammonium chloride toterminate the reaction, and extracted with ethyl acetate. The organiclayer was washed successively with water and saturated aqueous sodiumchloride and dried over anhydrous magnesium sulfate. The solvent wasdistilled off in vacuo to give a crude product of(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-4-tritylthioprolinal.

(Step 2)

To a solution of the compound obtained in Step 1 in tetrahydrofuran (25ml), sodium triacetoxyborohydride (1.42 g, 668 mmol), 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!aniline (1.61 g, 5.34 mmol) andacetic acid (0.306 ml, 5.34 mmol) were successively added at roomtemperature in a nitrogen stream. The reaction solution was stirred for20 hours and then saturated aqueous sodium hydrogencarbonate was addedthereto to terminate the reaction. This liquid mixture was extractedwith ethyl acetate. The organic layer was washed successively with waterand saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and concentrated in vacuo. The resulting residue was subjectedto silica gel column chromatography (Wakogel™ C-300 chloroform-ethylacetate 85:15) to give the title compound (1.57 g, yield 42.1%).

¹ H-NMR(CDCl₃)δ: 1.90-2.35(2 H,m),2.70-3-40(4 H,m),3.50-3.80(1H,m),3.84-4.04(1 H,m),4.24(2 H,d,J=5.6 Hz),⁴.95- 5.30(5 H,m),6.35-6.62(2H,m),6.90-7.80(21 H,m),8.05-8.30(4 H,m)

Reference Example 96

(2S,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-N-(p-nitrobenzyloxycarbonyl)anilinomethyl!pyrrolidine ##STR300## (Step1)

(2S,4R)-2-Anilinomethyl-N-t-butoxycarbonyl-4-t-butyldimethylsiloxypyrrolidine(995 mg, yield: 82%) was prepared as a yellow oily substance, from(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxyprolinal (990 mg, 3mmol) and aniline (0.3 ml, 3.3 mmol), in the same manner as in ReferenceExample 95-2.

¹ H-NMR(CDCl₃)δ: 0.05(6 H,s),0.86(9 H,s),1.49(9 H,s),1.70-2.11(3H,m),3.05-3.61(4 H,m),4.07-4.40(2 H,m),6.54-6.71(3 H,m),7.08-7.25(2 H,m)

(Step 2)

To a solution of the compound (945 mg, 2.3 mmol) obtained in Step 1 intetrahydrofuran (8 ml), N,N-diisopropylethylamine (0.8 ml, 4.6 mmol) andthen a solution of p-nitrobenzyloxycarbonyl chloride (750 mg, 3.45 mmol)in tetrahydrofuran (2 ml) were added dropwise in a nitrogen stream undercooling with ice. The reaction solution was stirred at the sametemperature for 2 hours and then concentrated in vacuo. Ethyl acetatewas added to the resulting residue. The organic layer was washedsuccessively with 1N aqueous potassium hydrogensulfate and saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, andconcentrated in vacuo. To the resulting residue, 2N hydrogenchloride-methanol solution (4 ml) was added. The reaction solution wasstirred at room temperature for 1.5 hours and then concentrated invacuo. Methanol was added to the resulting residue and then the volatilecomponents were distilled off in vacuo. To the resulting residue,dioxane-water solution (2:1, 9 ml) was added and the resulting solutionwas adjusted to pH 9.0 with 5N aqueous sodium hydroxide. While thesolution was maintained at pH 8.0-9.0 by using 1N aqueous sodiumhydroxide, a solution of p-nitrobenzyloxycarbonyl chloride (990 mg, 4.6mmol) in dioxane (4 ml) was added dropwise thereto under cooling withice. The reaction solution was poured into a liquid mixture of ethylacetate water. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, and concentratedin vacuo. The resulting residue was subjected to silica gel columnchromatography (Wakogel™ C-300 heptane-ethyl acetate=3:1) to give(2S,4R)-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)-2-N-(p-nitrobenzyloxycarbonyl)anilinomethyl!pyrrolidine (1 g, yield: 94%)as a yellow oily substance.

¹ H-NMR(CDCl₃)δ: 2.01-2.20(3 H,m),3.35-3.75(2 H,m),3.83-4.29(3H,m),4.40-4.55(1 H,m),5.05-5.21(4 H,m),7.10-7.45(9 H,m),8.05-8.20(4 H,m)

(Step 3)

To a solution of the compound (1 g, 2.16 mmol) obtained in Step 2 intetrahydrofuran (7 ml), triethylamine (0.45 ml, 3.24 mmol) andmethanesulfonyl chloride (0.25 ml, 3.24 mmol) were successively added ina nitrogen stream under cooling with ice. The resulting reactionsolution was stirred at the same temperature for 1.5 hours and broughttogether with water. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, and concentratedin vacuo to give (2S,4R)-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)-2-N-(p-nitrobenzyloxycarbonyl)anilinomethyl!pyrrolidine as a yellow oilysubstance, which was used for the next reaction without purification.

(Step 4)

To a solution of the compound obtained in Step 3 inN,N-dimethylformamide (6 ml), potassium thioacetate (428 mg, 4.32 mmol)was added. The resulting reaction solution was heated at 60° C. in anitrogen stream for 5 hours and then poured into a liquid mixture ofethyl acetate with water. The organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The resulting residue was subjected to silica gelcolumn chromatography (Wakogel™ C-300 heptane-ethyl acetate=1:1) to give(2S,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-N-(p-nitrobenzyloxycarbonyl)anilinomethyl!pyrrolidine (732 mg, yield:65%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ: 2.31(3 H,s),3.95-4.20(4 H,m),5.05(2 H,s), 5.19(2H,s),7.19-7.45(9 H,m),8.08-8.21(4 H,m)

Reference Example 97

(2S,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-N-(p-nitrobenzyloxycarbonyl)-3-(p-nitrobenzyloxycarbonyl)anilinomethyl!pyrrolidine##STR301## (Step 1)

(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-3-(ethoxycarbonyl)anilinomethyl!pyrrolidine (1.03 g, yield: 71%) wasprepared as a yellow oily substance, from(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy prolinal (1.0 g, 3.03mmol) and ethyl m-aminobenzoate (550 mg, 3.33 mmol), in the same manneras in Reference

Example 95-2

¹ H-NMR(CDCl₃)δ: 0.01(6 H,s),0.81(9 H,s),1.32-1.41(3 H,m), 1.43(9H,s),1.65-2.10(3 H,m),3.05-3.70(4 H,m),4.20-4.40(4 H,m),6.70-6.78(1H,m),7.03-7.31(3 H,m)

(Step 2)

To a solution of the compound (1.03 g, 2.15 mmol) obtained in Step 1 intetrahydrofuran (7 ml), N,N-diisopropylethylamine (0.75 ml, 4.30 mmol)and then a solution of p-nitrobenzyloxycarbonyl chloride (694 mg, 3.22mmol) in tetrahydrofuran (2 ml) were added dropwise in a nitrogen streamunder cooling with ice. The resulting reaction solution was stirred atthe same temperature for 1.5 hours, then concentrated in vacuo, anddissolved in ethyl acetate. The organic layer was washed successivelywith 1N aqueous potassium hydrogensulfate and saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, and concentrated invacuo. The resulting residue was subjected to silica gel columnchromatography (Wakogel™ C-300, heptane-ethyl acetate=2:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-3-ethoxycarbonyl-N-(p-nitrobenzyloxycarbonyl)anilinomethyl!pyrrolidine(1.17 g, yield: 89%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ: 0.03(6 H,s),0.85(9 H,s),1.22-1.50(12 H,m), 1.85-2.03(1H,m),3.20-3.42(2 H,m),3.88-4.23(4 H,m),4.25-4.50(2 H,m),5.22(2H,s),7.29-7.51(4 H,m),7.85-8.02(2 H,m),8.18(2 H,d,J=8.5 Hz)

(Step 3)

To a solution of the compound (1.1 g, 1.8 mmol) obtained in Step 2 inethanol (4.2 ml), 1N aqueous sodium hydroxide (1.8 ml, 1.8 mmol) wasadded. The resulting reaction solution was refluxed for 3 hours, thenbrought to room temperature, and acidified with 1N hydrochloric acid (2ml, 1.98 mmol). The liquid mixture was extracted with ethyl acetatethree times. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, and concentrated invacuo. The resulting residue was subjected to silica gel columnchromatography (Wakogel™ C-300, heptane-ethyl acetate=2:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-3-carboxy-N-(p-nitrobenzyloxycarbonyl)anilinomethyl!pyrrolidine (850 mg,yield: 81%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ: 0.01(6 H,s),0.81(9 H,s),1.31(9 H,s),1.82-2.01(2H,m),3.15-3.38(2 H,m),3.85-4.40(4 H,m), 5.20(2 H,s),7.27-7.55(4H,m),7.90-8.05(2 H,m),8.15(2 H,d,J=8-3 Hz)

(Step 4)

To a solution of the compound (850 mg, 1.45 mmol) obtained in Step 3 indichloromethane (4 ml), 4-(dimethylamino)pyridine (35 mg, 0.29 mmol),p-nitrobenzyl alcohol (263 mg, 1.72 mmol) and1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride weresuccessively added in a nitrogen stream under cooling with ice. Theresulting reaction solution was stirred at room temperature for 15 hoursand then concentrated in vacuo. Ethyl acetate was added to the resultingresidue and the organic layer was washed successively with 1N aqueouspotassium hydrogensulfate and saturated aqueous sodium chloride, driedover anhydrous sodium sulfate, and then concentrated in vacuo. Theresulting residue was subjected to silica gel column chromatography(Wakogel™ C-300, heptane-ethyl acetate=3:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-N-(p-nitrobenzyloxycarbonyl)-3-(p-nitrobenzyloxycarbonyl)anilinomethyl!pyrrolidine(910 mg, yield: 87%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ: 0.01(6 H,s),0.83(9 H,s),1.57(9 H,s),1.80-2.01(2H,m),3.20-3.40(2 H,m),3.87-4.40(4 H,m), 5.21(2 H,s),5.47(2H,s),7.30-7.65(6 H,m),7.90-8.30(6 H,m)

(Step 5)

(2S,4R)-4-Hydroxy-N-(p-nitrobenzyloxycarbonyl)-2-N-(p-nitrobenzyloxycarbonyl)-3-(p-nitrobenzyloxycarbonyl)anilinomethyl!pyrrolidine(775 mg, yield: 90%) was prepared as a yellow oily substance from thecompound (850 mg, 1.18 mmol) obtained in Step 4 in the same manner as inReference Example 96-2.

¹ H-NMR(CDCl₃)δ: 1.45-1.70(2 H,m),3.30-3.69(2 H,m),3.88-4.35(4H,m),4.40-4.55(1 H,m),5.01-5.25(4 H,m),5.40-5.49(2 H,m),7.25-7.63(8H,m),7.85-8.28(8 H,m)

(Step 6)

(2S,4R)-4-Mesyloxy-N-(p-nitrobenzyloxycarbonyl)-2-N-(p-nitrobenzyloxycarbonyl)-3-(p-nitrobenzyloxycarbonyl)anilinomethyl!pyrrolidinewas prepared as a yellow oily substance from the compound (775 mg, 1.06mmol) obtained in Step 5 in the same manner as in Reference Example96-3, which was used for the next reaction without purification.

(Step 7)

(2S,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-N-(p-nitrobenzyloxycarbonyl)-3-(p-nitrobenzyloxycarbonyl)anilinomethyl!pyrrolidine(410 mg, yield: 50%) was prepared as a yellow oily substance from thecompound obtained in Step 6 in the same manner as in Reference Example96-4.

¹ H-NMR(CDCl₃)δ: 2.05(3 H,s),3.08-3.22(1 H,m),3.80-4.21(7H,m),5.02-5.50(6 H,m),7.25-7.63(8 H,m),7.85-8.30(8 H,m)

In the following Reference Examples 98 to 99, physicochemical data ofthe compounds used in Examples as thiols or thiol precursors are shown.

Reference Example 98 ##STR302##

¹ H-NMR(CDCl₃)δ: 2.33(3 H,s),3.36(1 H,m),3.56(1 H,m), 3.80(2 H,m),3.93(1H,m),4.20-4.35(2 H,m),4.59(2 H,m), 5.15-5.25(2 H,m),5.91(1 H,m),6.61(2H,d,J=7.5 Hz), 6.77(1 H,t,J=7.5 Hz),7.17(2 H,d,J=7.5 Hz)

Reference Example 99 ##STR303##

IR(KBr)cm⁻¹ : 3743,1693,1517,1344

¹ H-NMR(CDCl₃)δ: 1.68-1.84(1 H,m),1.81(1 H,d,J=6.6 Hz),2.70-2.85(1H,m),3.19-3.61(4 H,m),4.12-4.25(1 H,m),4.43-4.55(1 H,m),4.72(2 H,d,J=5.5Hz),5.04(1 H,br s),5.19-5.36(4 H,m),6.11(1 H,br s),6.45(1 H,d,J=7.7Hz),7.23-7.33(1 H,m),7.40-7.57(6 H,m),7.84-7.97(2 H,m),8.19-8.26(4 H,m)

Reference Example 100

(2S,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!phenoxymethyl!-pyrrolidine##STR304## (Step 1)

N,N-Diisopropylethylamine (21.1 ml, 121 mmol) and mesyl chloride (4.67ml, 60.3 mmol) were successively added to a solution of(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-hydroxymethylpyrrolidine(10.2 g, 30.2 mmol; the compound of Reference Example 1-3) in EuropeanLaid Open Patent Application No. 449191) in methylene chloride (200 ml)in a nitrogen stream under cooling with ice and the resulting liquidmixture was stirred at the same temperature for 30 minutes. To thisreaction solution, saturated aqueous ammonium chloride was added toterminate the reaction. The reaction mixture was extracted with ethylacetate. The organic layer was washed successively with saturatedaqueous sodium hydrogencarbonate and saturated aqueous sodium chlorideand dried over anhydrous sodium sulfate. The solvent was distilled offto obtain(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(mesyloxymethyl)pyrrolidineas the residue.

¹ H-NMR(CDCl₃)δ: 0.06(6 H,s),0.86(9 H,s),1.46(9 H,s),1.95-2.10(2H,m),2.99(3 H,s),3.30-3.40(2 H,m),4.05-4.61(4 H,m)

(Step 2)

To a solution of methyl p-hydroxybenzoate (2.22 g, 1.46 mmol) inN,N-dimethylformamide (80 ml), sodium hydride (635 mg, 15.9 mmol) wasadded in a nitrogen stream at room temperature and then(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(mesyloxymethyl)pyrrolidine(5.00 g, 12.2 mmol) was added at the same temperature. The resultingreaction solution was stirred at 60° C. for 10 hours. Saturated aqueousammonium chloride was added to the reaction solution to terminate thereaction. This liquid mixture was extracted with ethyl acetate and theorganic layer was washed successively with water and saturated aqueoussodium chloride and dried over anhydrous magnesium sulfate. The solventwas distilled off in vacuo and the resulting residue was subjected tosilica gel column chromatography (Wakogel™ C-300, heptane-ethylacetate=85:15) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-4-methoxycarbonyl)phenoxymethyl!pyrrolidine (3.62 g, yield: 63.7%).

¹ H-NMR(CDCl₃)δ: 0.07(6 H,s),0.87(9 H,s),1.45(9 H,s),1.96-2.18(2H,m),3.26-3.50(2 H,m),3.87(3 H,s),3.96-4.32(3 H,m),4.41-4.52(1H,m),6.90(2 H,d,J=8.6 Hz), 7.96(2 H,d,J=8.6 Hz)

(Step 3)

To a solution of the compound (2.00 g, 3.41 mmol) obtained in thepreceding step in tetrahydrofuran (40 ml), lithium aluminum hydride (388mg, 10.2 mmol) was added in a nitrogen stream under cooling with ice.The resulting reaction solution was stirred at the same temperature for2 hours and then sodium sulfate decahydrate (20 g) was added toterminate the reaction. The insolubles were filtered off and thefiltrate was concentrated in vacuo to give a crude product of(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-4-hydroxymethyl)phenoxymethyl!pyrrolidine.

(Step 4)

To a solution of the crude product obtained in the preceding step inmethylene chloride (40 ml), triethylamine (2.39 ml, 13.7 mmol) and mesylchloride (0.529 ml, 6.83 mmol) were successively added in a nitrogenstream under cooling with ice and the resulting liquid mixture wasstirred at the same temperature for 2 hours. Saturated aqueous sodiumhydrogencarbonate was added to the reaction solution and the liquidmixture was extracted with chloroform. The organic layer was washedsuccessively with water and saturated aqueous sodium sulfate, dried overanhydrous sodium sulfate, and then concentrated in vacuo to give a crudeproduct of (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-4-mesyloxymethyl)phenoxymethyl!pyrrolidine.

(Step 5)

To a solution of the crude product obtained in the preceding step inN,N-dimethylformamide (20 ml), sodium azide (666 mg, 10.2 mmol) wasadded in a nitrogen stream under cooling with ice and the resultingliquid mixture was stirred for 2 hours. Saturated aqueous ammoniumchloride was added to the reaction solution to terminate the reaction.This liquid mixture was extracted with ethyl acetate. The organic layerwas washed successively with water and saturated aqueous sodium chlorideand then dried over anhydrous magnesium sulfate. The solvent wasdistilled off in vacuo and the resulting residue was subjected to silicagel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=9:1) togive(2S,4R)-2-(4-azidomethyl)phenoxymethyl-N-t-butoxycarbonyl-(4-t-butyldimethylsiloxy)pyrrolidine(1.01 g, yield: 50.8%).

¹ H-NMR(CDCl₃)δ: 0.07(6 H,s),0.88(9 H,s),1.46(9 H,s),1.96-2.22(2H,m),3.25-3.60(2 H,m),3.90-4.40(3 H,m), 4.26(2 H,s),4.45-4.57(1H,m),6.90(2 H,d,J=8.3 Hz), 7.25(2 H,d,J=8.3 Hz)

(Step 6)

To a solution of the compound (1.02 g, 1.75 mmol) obtained in thepreceding step in tetrahydrofuran (15 ml), triphenylphosphine (505 mg,1.93 mmol) and water (0.063 ml, 3.50 mmol) were successively added in anitrogen stream at room temperature. After 12 hours of stirring at thesame temperature, to this reaction solution under cooling with ice,N,N-diisopropylethylamine (0.610 ml, 3.50 mmol) andp-nitrobenzyloxycarbonyl chloride (370 mg, 1.93 mmol) were successivelyadded. The resulting liquid mixture was stirred at the same temperaturefor 15 minutes. Saturated aqueous ammonium chloride was added to thisreaction solution to terminate the reaction and the liquid mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and concentrated in vacuo. The resulting residue was subjected to silicagel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=6:4) togive (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!phenoxymethyl!-pyrrolidine (1.02g, yield: 75.9%).

¹ H-NMR(CDCl₃)δ: 0.07(6 H,s),0.88(9 H,s),1.45(9 H,s),1.97-2.26(2H,m),3.25-3.51(2 H,m),3.90-4.40(3 H,m), 4.31(2 H,d,J=5.9 Hz),4.44-4.56(1H,m),5.09-5.20(1 H,m), 5.21(2 H,s),6.86(2 H,d,J=8.1 Hz),7.19(2 H,d,J=8.1Hz), 7.50(2 H,d,J=8.2 Hz),8.20(2 H,d,J=8.2 Hz)

(Step 7)

To the compound obtained in the preceding step, 2.17 N hydrogenchloride-methanol solution (15 ml) was added. The resulting reactionsolution was stirred in a nitrogen stream at room temperature for 10hours and then concentrated in vacuo. The resulting residue wasdissolved in dioxane-water (2:1, 30 ml) and this resulting solution wasadjusted to pH 10 with 1N aqueous sodium hydroxide. While the solutionwas maintained at pH 9-10 by using 1N aqueous sodium hydroxide, asolution of p-nitrobenzyloxycarbonyl chloride (385 mg, 2.01 mmol) indioxane (3 ml) was added dropwise thereto. The reaction solution waspoured into a liquid mixture of ethyl acetate-water. The organic layerwas washed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and then concentrated in vacuo. The resulting residuewas subjected to silica gel column chromatography (Wakogel™ C-300,heptane-ethyl acetate=25:75) to give(2S,4R)-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!phenoxymethyl!-pyrrolidine (918mg, yield 94.5%).

¹ H-NMR(CDCl₃)δ: 2.00-2.40(2 H,m),3.53-3.76(2 H,m),3.96-4.17(1H,m),4.32(2 H,d,J=5.9 Hz),4.25-4.45(1 H,m),4.54-4.70(1 H,m),4.96-5.42(5H,m),6.70-6.93(2 H,m),7.11-7.24(2 H,m),7.35-7.60(4 H,m),8.02-8.30(4 H,m)

(Step 8)

To a solution of the compound obtained in the preceding step inmethylene chloride (20 ml), N,N-diisopropylethylamine (1.09 ml, 6.23mmol) and mesyl chloride (0.241 ml, 3.11 mmol) were successively addedin a nitrogen stream under cooling with ice and the resulting liquidmixture was stirred at the same temperature for 2 hours. Saturatedaqueous ammonium chloride was added to the reaction solution toterminate the reaction. This liquid mixture was extracted with ethylacetate. The organic layer was washed successively with water andsaturated aqueous sodium chloride and then dried over anhydrousmagnesium sulfate. The solvent was distilled off to give a crude productof (2S,4R)-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!phenoxymethyl!-pyrrolidine.

(Step 9) To a solution of the crude product obtained in the precedingstep in N,N-dimethylformamide (30 ml), potassium thioacetate (534 mg,4.67 mmol) was added in a nitrogen stream at room temperature and theresulting reaction solution was stirred at 60° C. for 3 hours. Saturatedaqueous ammonium chloride was added to this reaction solution toterminate the reaction. This liquid mixture was extracted with ethylacetate. The organic layer was washed successively with water andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and concentrated in vacuo. The resulting residue was subjected to silicagel chromatography (Wakogel™ C-300, heptane-ethyl acetate=1:1) to givethe title compound (802 mg, yield 80.6%).

¹ H-NMR(CDCl₃)δ: 2.00-2.18(1 H,m),2.50-2.70(1 H,m),3.24-3.35(1H,m),3.80-4.40(5 H,m),4.30(2 H,d,J=5.8 Hz),4.90-5.50(5 H,m),6.70-7.00(2H,m),7.00-7.30(2 H,m),7.30-7.60(4 H,m),8.00-8.30(4 H,m)

Reference Example 101

(2S,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-4-(phenoxymethyl)pyrrolidine##STR305## (Step 1)

Sodium hydride (60% dispersion in mineral oil, 300 mg, 7.50 mmol) wasadded to a solution of phenol (710 mg, 7.54 mmol) inN,N-dimethylformamide (10 ml). The resulting reaction solution wasstirred at room temperature for 30 minutes and then a solution of(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(mesyloxymethyl)pyrrolidine(2.05 g, 5.00 mmol) in N,N-dimethylformamide (5 ml) was added thereto.The resulting liquid mixture was stirred at 70° C. overnight. Thereaction solution was poured into a liquid mixture of water with ethylacetate. The organic layer was washed with 1N aqueous potassiumhydrogensulfate and saturated aqueous sodium chloride, dried overanhydrous sodium sulfate, and then concentrated in Vacuo. The resultingresidue was subjected to silica gel column chromatography (Wakogel™C-300, heptane-ethyl acetate=4:1→1:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(phenoxymethyl)pyrrolidine(1.23 g, yield 60%) as a pale yellow oily substance.

¹ H-NMR(CDCl₃)δ: 0.07(6 H,s),0.88(9 H,s),1.45(9 H,s),1.95-2.20(2H,m),3.25-3.50(2 H,m),3.90-4.30(3 H,m),4.40-4.60(1 H,m),6.80-7.00(3H,m),7.19-7.32(2 H,m)

(Step 2)

A solution of the compound (1.22 g, 2.97 mmol) obtained in Step 1 in2.0N hydrogen chloride-methanol (50 ml) was stirred at room temperaturefor 5 hours and then this reaction solution was concentrated in vacuo.To the resulting residue, methanol was added and then the volatilecomponents were distilled off in vacuo. A solution of the resultingresidue in dioxane-water (2:1, 30 ml) was adjusted to pH 9.0 with 5Naqueous sodium hydroxide. While this solution was maintained at pH9.0-8.0 by using 5N aqueous sodium hydroxide, a solution ofp-nitrobenzyloxycarbonyl chloride (780 mg, 3.56 mmol) in dioxane (5 ml)was added dropwise under cooling with ice. The reaction solution waspoured into a liquid mixture of ethyl acetate-water. The organic layerwas washed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and then concentrated in vacuo. The resulting residuewas subjected to silica gel column chromatography (Wakogel™ C-300,heptane-ethyl acetate=4:1→1:1) to give(2S,4R)-4-hydroxy-2-phenoxymethyl-N-((p-nitrobenzyloxycarbonyl)pyrrolidine(1.12 g, yield 100%) as a pale yellow oily substance.

¹ H-NMR(CDCl₃)δ: 3.35-3.75(2 H,m),4.00-4.45(3 H,m),4.55-4.70(1H,m),5.21(2 H,s),6.75-7.00(3 H,m),7.20-7.30(2 H,m),7.40-7.50(2H,m),8.05-8.20(2 H,m)

(Step 3)

To a solution of the compound (1.11 g, 2.96 mmol) obtained in Step 2 intetrahydrofuran (20 ml), triethylamine (630 μl, 4.44 mmol) andmethanesulfonyl chloride (280 μl, 3.55 mmol) were successively added ina nitrogen stream under cooling with ice and the resulting reactionsolution was stirred at the same temperature for 1.5 hours. Water wasadded to the reaction solution and then the organic layer was washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and then concentrated in vacuo to give a crude product of(2S,4R)-4-mesyloxy-2-phenoxymethyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(1.4 g) as a yellow oily residue, which was used for the next reactionwithout purification.

(Step 4)

To a solution of the crude product (1.4 g) obtained in Step 3 inN,N-dimethylformamide (15 ml), potassium thiosulfate (683 mg, 5.98 mmol)was added. The resulting reaction solution was heated at 70° C. in anitrogen stream for 8 hours and then poured into a liquid mixture ofethyl acetate with water. The organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated in vacuo. The resulting residue was subject to silica gelcolumn chromatography (Wakogel™ C-300, heptane-ethyl acetate=9:1→2: 1)to give(2S,4S)-4-acetylthio-2-(phenoxymethyl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(1.23 g, yield 96%) as a pale yellow oily substance.

¹ H-NMR(CDCl₃)δ: 2.34(3 H,s),3.25-3.35(1 H,m),3.70-4.35(7 H,m),5.21(2H,s),6.80-7.00(2 H,m),7.21-7.35(3 H,m),7.43-7.53(2 H,m),8.10-8.25(2 H,m)

In the following Reference Example 102, physicochemical data of acompound used in Examples as a thiol or a thiol precursor are shown.

Reference Example 102 ##STR306##

¹ H-NMR(CDCl₃)δ: 2.34(3 H,s),3.52(1 H,m),3.65-3.85(2 H,m), 3.98(1 H,brt,J=8.5 Hz),4.22(1 H,m),4.58(2 H,m), 4.85(2 H,m),5.15-5.35(2 H,m),5.90(1H,m), 6.85(2 H,m),6.88(1 H,br t,J=7.5 Hz),7.27(2 H,m)

Reference Example 103

(2R,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!phenethyl!-pyrrolidine##STR307## (Step 1)

1.6M Butyl lithium-hexane solution (72.5 ml, 116 mmol) was addeddropwise to a solution of 4-(t-butyldimethylsiloxymethyl)bromobenzene(35.0 g, 116 mmol) in tetrahydrofuran (700 ml) in a nitrogen stream at-78° C. over 5 minutes. The resulting reaction solution was stirred for10 minutes and then a solution of(2S,4S)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(formylmethyl)pyrrolidine(26.6 g, 77.4 mmol) in tetrahydrofuran (100 ml) was dropwise addedthereto. The reaction solution was stirred for 20 minutes and saturatedaqueous ammonium chloride was added thereto. The resulting liquidmixture was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and concentrated in vacuo. The resulting residue was dissolvedin a solvent mixture of tetrahydrofuran-methanol (10:1 220 ml) andtreated with sodium boron hydride (1.46 g, 38.7 mmol) at roomtemperature. The reaction solution was stirred for 18 hours and then 10%aqueous citric acid was added to terminate the reaction. The liquidmixture was extracted with ethyl acetate. The organic layer was washedsuccessively with saturated aqueous sodium hydrogencarbonate andsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and concentrated in vacuo. The resulting residue was subjectedto silica gel column chromatography (Wakogel™ C-300 heptane-ethylacetate 92:8→85:15) to give(2R,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2- (2R)-2- hydroxy-4-(t-butyldimethylsiloxymethyl)phenyl!!ethyl!pyrrolidine diastereomer(less polar compound 13.1 g, yield: 31.5%) and diastereomer B (polarcompound 13.4 g, yield: 32.2%).

Diastereomer A

¹ H-NMR(CDCl₃)δ:0.06(6H,s),0.10(6H,s),0.88(9H,s),0.94(9H,s),1.49(9H,s),1.50-1.80(3H,m),1.98-2.10(1H,m),3.35-3.45(2H,m),4.30-4.45(2H,m),4.60-4.80(2H,m),4.72(2H,s),5.20-5.30(1H,m),7.28(2H,d,J=8.5Hz),7.34(2H,d,J=8.5Hz)

Diastereomer B

¹ H-NMR(CDCl₃)δ:0.05(6H,s),0.09(6H,s),0.87(9H,s),0.94(9H,s),1.46(9H,s),1.30-1.60(1H,m),1.65-1.80(2H,m),2.00-2.20(1H,m),3.30-3.50(2H,m),4.00-4.40(2H,m),4.60-4.85(1H,m),4.72(2H,s),7.20-7.40(4H,m)

(Step 2)

To a solution of the diastereomer A (3.00 g, 5.58 mmol) obtained in Step1 in methylene chloride, N,N-diisopropylethylamine (2.91 ml, 16.7 mmol)and mesyl chloride (0.648 ml, 8.37 mmol) were successively added in anitrogen stream under cooling with ice and the resulting reactionsolution was stirred at the same temperature for 2 hours. Saturatedaqueous ammonium chloride was added to this reaction solution toterminate the reaction and the liquid mixture was extracted with ethylacetate. The organic layer was washed successively with water, saturatedaqueous sodium hydrogencarbonate and saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, and then concentrated in vacuo. Theresulting residue was subjected to silica gel column chromatography(Wakogel™ C-300, heptane-ethyl acetate 75:25→65:35) to give(4S,6R,8R)-8-t-butyldimethylsiloxy-4-4-(t-butyldimethylsiloxymethyl)phenyl!-1-aza-3-oxabicyclo4.3.0!nonan-2-one (967 mg, yield: 37.4%).

¹H-NMR(CDCl₃)δ:0.00(12H,s),0.81(9H,s),0.84(9H,s),1.40-1.60(2H,m),1.95-2.04(1H,m),2.28-2.37(1H,m),3.29-3.33(1H,m),3.75(1H,dd,J=4.6&12.2Hz),3.93-4.06(1H,m),4.37-4.42(1H,m),4.64(2H,s),5.22(1H,dd,J=2.2&11.7Hz),7.22(2H,d,J=8.8Hz), 7.26(2H,d,J=8.8Hz)

(Step 3)

To a solution of the compound (824 mg, 1.78 mmol) obtained in Step 2 ina mixture of tetrahydrofuran-methanol (1:1, 30 ml), 10% palladium-carboncatalyst (420 mg) was added and the resulting reaction mixture wasstirred at room temperature in a hydrogen stream for 18 hours. Thecatalyst was separated from the reaction mixture by filtration and thefiltrate was concentrated in vacuo to give a crude product of(2R,4R)-4-t-butyldimethylsiloxy-2-4-(t-butyldimethylsiloxymethyl)phenethyl!pyrrolidine.

(Step 4)

The crude product obtained in Step 3 was dissolved in water-dioxane(1:1, 20 ml) and the resulting solution was adjusted to pH 10 with 1Naqueous sodium hydroxide. While this solution was maintained at pH 9-10by using 1N aqueous sodium hydroxide, a solution ofp-nitrobenzyloxycarbonyl chloride (374 mg, 1.95 mmol) in dioxane (5 ml)was added dropwise thereto under cooling with ice. The reaction solutionwas poured into a liquid mixture of ethyl acetate-water. The organiclayer was washed with saturated aqueous sodium chloride and dried overanhydrous sodium sulfate. The solvent was distilled off in vacuo to givea crude product of (2R,4R)-4-t-butyldimethylsiloxy-2-4-(t-butyldimethylsiloxymethyl)phenethyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidine.

(Step 5)

A solution of the crude product obtained in Step 4 in 2.17M hydrogenchloride-methanol (30 ml) was stirred at room temperature for 24 hours.The reaction solution was concentrated in vacuo and then diluted withethyl acetate-water. The organic layer was washed successively withwater and saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, and then concentrated in vacuo. The resulting residuewas subjected to silica gel column chromatography (Wakogel™ C-300heptane-ethyl acetate 2:8) to give (2R,4R)-4-hydroxy-2-4-(hydroxymethyl)phenethyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (532mg, yield: 74.8%).

¹H-NMR(CDCl₃)δ:1.50-1.95(4H,m),2.05-2.45(2H,m),2.45-2.65(2H,m),3.35-3.55(1H,m),3.55-3.75(1H,m),3.95-4.15(1H,m),4.40-4.50(1H,m),4.63(2H,s),5.05-5.30(2H,m),6.90-7.35(4H,m),7.35-7.60(2H,m),8.05-8.30(2H,m)

(Step 6)

To a solution of the .compound (520 mg, 1.30 mmol) obtained in thepreceding step in methylene chloride, N,N-diisopropylethylamine (1.36ml, 7.79 mmol) and mesyl chloride (0.302 ml, 3.90 mmol) weresuccessively added in a nitrogen stream under cooling with ice. Thisreaction solution was stirred at the same temperature for 1 hour andthen saturated aqueous ammonium chloride was added thereto to terminatethe reaction. This liquid mixture was extracted with ethyl acetate,washed successively with water and saturated aqueous sodium chloride,and then dried over anhydrous magnesium sulfate. The solvent wasdistilled off in vacuo to give a crude product of (2R,4R)-4-mesyloxy-2-4-(mesyloxymethyl)phenethyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidine.

(Step 7)

To a solution of the crude product obtained in Step 6 inN,N-dimethylformamide (10 ml), sodium azide (101 mg, 1.56 mmol) wasadded in a nitrogen stream under cooling with ice and the resultingreaction mixed solution was stirred at the same temperature for 2 hours.To this reaction solution, saturated aqueous ammonium chloride was addedto terminate the reaction and the liquid mixture was extracted withethyl acetate. The organic layer was washed successively with water andsaturated aqueous sodium chloride and dried over anhydrous magnesiumsulfate. The solvent was distilled off to give a crude product of(2R,4R)-2-4-(azidomethyl)phenethyl!-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine.

(Step 8)

To a solution of the crude product obtained in Step 7 in tetrahydrofuran(10 ml), triphenylphosphine (375 mg, 1.43 mmol) and water (46.8 μl, 2.60mmol) were successively added in a nitrogen stream at room temperature.The reaction solution was stirred at the same temperature for 12 hoursand then N,N-diisopropylethylamine (0.679 ml, 3.89 mmol) andp-nitrobenzyloxycarbonyl chloride (273 mg, 1.43 mmol) were successivelyadded thereto under cooling with ice. The reaction solution was stirredfor another 1 hour. Saturated aqueous ammonium chloride was added tothis reaction solution to terminate the reaction and the resultingliquid mixture was extracted with ethyl acetate. The organic layer waswashed successively with water and saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, and then concentrated in vacuo.The resulting residue was subjected to silica gel column chromatography(Wakogel™ C-300 heptane-ethyl acetate 4:6) to give(2R,4R)-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!phenethyl!-pyrrolidine (552 mg,yield: 64.7%).

¹ H-NMR(CDCl₃)δ:1.60-1.80(1H,m),1.90-2.70(5H,m),3.02(3H,s),3.50-3.67(1H,m),3.97-4.16(2H,m),4.34(2H,d,J=6.4Hz),5.10-5.40(6H,m),7.00-7.30(4H,m),7.40-7.60(4H,m),8.10-8.30(4H,m)

(Step 9)

To a solution of the compound (540 mg, 0.822 mmol) obtained in Step 8 inN,N-dimethylformamide (20 ml), potassium thioacetate (235 mg, 2.06 mmol)was added in a nitrogen stream at room temperature and the resultingreaction mixed solution was stirred at 55° C. for 3 hours. Saturatedaqueous ammonium chloride was added to this reaction solution toterminate the reaction. This liquid mixture was extracted with ethylacetate. The organic layer was washed successively with water andsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and then concentrated in vacuo. The resulting residue wassubjected to silica gel column chromatography (Wakogel™ C-300hexane-ethyl acetate 1:1) to give(2R,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxyoarbonyl)aminomethyl!phenethyl!-pyrrolidine (505 mg,yield: 96.5%).

¹H-NMR(CDCl₃)δ:1.60-1.90(2H,m),2.50(3H,s),2.46-2.70(3H,m),3.17-3.26(1H,m),3.82-4.02(2H,m),4.08-4.18(1H,m),4.36(2H,d,J=5.9Hz),5.07-5.32(6H,m),7.00-7.30(4H,m),7.40-7.60(4H,m),8.12-8.34(4H,m)

REFERENCE EXAMPLE 104

(2R,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!benzyl!-pyrrolidine ##STR308##(Step 1)

(2S,4R)-N-t-Butoxycarbonyl-4-(t-butyldimethylsiloxy)-2-α-hydroxy-4-(tetrahydropyranyloxymethyl)benzyl!-pyrrolidine (7.67 g,yield: 57.7%) was prepared as a yellow oily substance from(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (8.37 g,25.4 mmol) and -4-(tetrahydropyranyloxymethyl)bromobenzene (13.8 g, 50.9mmol) in the same manner as in Reference Example 103-1.

¹ H-NMR(CDCl₃)δ:0.03(6H,s),0.85(9H,s),1.28-2.11(17H,m),3.20-3.63(3H,m),3.78-4.59(4H,m),4.69-4.93(3H,m),7.22-7.45(4H,m)

(Step 2)

To a solution of the compound (7.67 g, 14.7 mmol) obtained in Step 1 andimidazole (10 mg, 0.15 mmol) in tetrahydrofuran (150 ml), 60% sodiumhydride (825 mg, 20.6 mmol) was added in a nitrogen stream at roomtemperature and the reaction solution was stirred for 20 minutes. Then,carbon disulfide (2.65 g, 44 mmol) was added and the reaction solutionwas stirred for 30 minutes. Methyl iodide (1.84 ml, 29.6 mmol) was addedto the reaction solution and the reaction solution was stirred for 30minutes and then poured into a liquid mixture of 10% aqueous citric acidwith ethyl acetate. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, and concentratedin vacuo. The resulting residue was subjected to silica gel columnchromatography (Wakogel™ C-300 heptane-ethyl acetate 8:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-α-(methylthiothiocarbonyloxy)-4-(tetrahydropyranyloxymethyl)benzyl!pyrrolidine(4.01 g, yield: 44.6%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ:0.07(6H,s),0.87(9H,s),1.40-2.21(17H,m),2.65(3H,s),3.01-4.03(5H,m),4.36-4.70(2H,m),4.73-4.89(2H,m),7.19-7.52(4H,m)

(Step 3)

To a solution of the compound (4.01 g, 6.56 mmol) obtained in Step 2 intoluene (80 ml), catalytic amounts of 2,2'-azobisisobutyronitrile andtributyltin hydride (12.0 ml, 44.6 mmol) were successively added in annitrogen stream and the resulting reaction solution was refluxed for 15hours. After addition of aqueous potassium fluoride at room temperature,the reaction solution was filtered through celite and the filtrate waspoured into a liquid mixture of ethyl acetate with water. The organiclayer was washed with saturated aqueous sodium sulfate, dried overanhydrous sodium sulfate, and concentrated in vacuo. The resultingresidue was subjected to silica gel column chromatography (Wakogel™C-300 heptane-ethyl acetate 8:1) to give(2R,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-4-(tetrahydropyranyloxymethyl)benzyl!pyrrolidine (3.29 g, yield: 99.3%)as a yellow oily substance.

¹ H-NMR(CDCl₃)δ:0.00(6H,s),0.82(9H,s),1.21-1.97(17H,m),2.61-2.82(1H,m),2.98-3.62(4H,m),3.89-4.25(3H,m),4.46(1H,d,J=11.9Hz),4.68-4.81(2H,m),7.06-7.37(4H,m)

(Step 4)

To a solution of the compound (3.29 g, 6.51 mmol) obtained in Step 3 inmethanol (250 ml), pyridinium p-toluenesulfonate (160 mg, 0.64 mmol) wasadded at room temperature in a nitrogen stream. The resulting reactionsolution was stirred at 50° C. for 3.5 hours and then concentrated invacuo. The resulting residue was poured into a liquid mixture of ethylacetate with water. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, and concentratedin vacuo. The residue was subjected to silica gel column chromatography(Wakogel™ C-300 heptane-ethyl acetate 4:1) to give(2R,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-hydroxymethyl)benzyl!pyrrolidine (2.1 g, yield: 76.6%) as a yellowoily substance.

¹H-NMR(CDCl₃)δ:0.01(6H,s),0.84(9H,S),1.53(9H,s),1.68-1.91(2H,m),2.60-2.82(1H,m),2.99-3.41(3H,m),3.97-4.26(2H,m),4.69(2H,s),7.10-7.40(4H,m)

(Step 5)

To a solution of the compound (2.1 g, 4.99 mmol) obtained in Step 4 intetrahydrofuran (30 ml), triethylamine (880 μl, 6.31 mmol) and mesylchloride (480 μl, 6.20 mmol) were successively added a nitrogen streamunder cooling with ice. The reaction solution was stirred at the sametemperature for 30 minutes and then poured into a liquid mixture ofethyl acetate with water. The organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate andconcentrated in vacuo to give(2R,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-mesyloxymethylbenzyl)pyrrolidineas a yellow oily residue, which was used for the next reaction withoutpurification.

(Step 6)

(2R,4R)-2-(4-Azidomethylbenzyl)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)pyrrolidine(2.05 g, yield: 92.1%) was prepared as a yellow oily substance from thecompound obtained in Step 5 and sodium azide (405 mg, 6.23 mmol), in thesame manner as in Example 103-7.

¹H-NMR(CDCl₃)δ:0.01(6H,s),0.84(9H,s),1.53(9H,s),1.70-1.90(2H,m),2.63-2.86(1H,m),2.98-3.42(3H,m),3.95-4.24(2H,m),4.34(2H,s),7.11-7.32(4H,m)

(Step 7)

To a solution of the compound (2.05 g, 4.6 mmol) obtained in Step 6 intetrahydrofuran (20 ml), water (170 μl, 9.44 mmol) andtriphenylphosphine (1.5 g, 5.72 mmol) were successively added at roomtemperature in a nitrogen stream and the resulting reaction solution wasstirred at the same temperature for 17 hours. Then, the reactionsolution was concentrated in vacuo and the resulting yellow oily residuewas dissolved in 2.17N hydrogen chloride-methanol solution (17 ml). Theresulting solution was stirred at room temperature for 3 hours and thenconcentrated in vacuo. Dichloromethane was added to the residue and thevolatile components were distilled off in vacuo to give a yellow oilyresidue containing (2R,4R)-2-(4-aminomethylbenzyl)-4-hydroxypyrrolidinedihydrochloride, which was used for the next reaction withoutpurification.

(Step 8)

A solution of the compound obtained in Step 7 in dioxane-water (1:1, 60ml) was adjusted to pH 9.0 with 1N aqueous sodium hydroxide. While thissolution was maintained at pH 8.0-9.0 by using 1N aqueous sodiumhydroxide, a solution of p-nitrobenzyloxycarbonyl chloride (2.1 g, 10.4mmol) in dioxane (5 ml) was added thereto dropwise. The reactionsolution was poured into a liquid mixture of ethyl acetate-water. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous sodium sulfate, and then concentrated in vacuo. Theresulting residue was subjected to silica gel column chromatography(Wakogel™ C-300 heptane-ethyl acetate 1:4) to give (2R,4R)-4-hydroxy-2-4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!benzyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(2.9 g, containing triphenylphosphine oxide) as a yellow oily substance.

¹H-NMR(CDCl₃)δ:1.60-2.00(2H,m),2.69-2.80(1H,m),3.03-3.68(3H,m),4.20-4.32(2H,m),4.36(2H,d,j=5.9Hz),5.23(2H,s),5.28(2H,s),7.02-7.23(4H,m),8.18-8.30(4H,m)

(Step 9)

To a solution of the compound (2.9 g) obtained in Step 8 intetrahydrofuran (30 ml), triethylamine (670 μl, 4.81 mmol) and mesylchloride (370 μl, 4.78 mmol) were successively added in a nitrogenstream under cooling with ice. The resulting reaction solution wasstirred at the same temperature for 1 hour and then poured into a liquidmixture of ethyl acetate with water. The organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and concentrated in vacuo. The resulting residue was subjected to silicagel column chromatography (Wakogel™ C-300 heptane-ethyl acetate 1:2) togive (2R,4R)-4-mesyloxy-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!benzyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(2.4 g, yield: 81.1%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ:1.92-2.38(2H,m),2.72-2.88(1H,m),2.98(3H,s),3.02-3.50(2H,m),3.88-4.00(1H,m),4.25-4.43(3H,m),4.92(1H,brs),5.23(2H,s),5.29(2H,s),7.00-7.23(4H,m),8.12-8.30(4H,m)

(Step 10)

(2R,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2- 4-N-(p-nitrobenzyloxycarbonyl)aminomethyl!benzyl!-pyrrolidine (1.83 g,yield: 78.8%) was prepared as a red oily substance from the compound(2.4 g, 3.73 mmol) obtained in Step 9 and potassium thioacetate (930 mg,8.16 mmol) in the same manner as in Reference Example 103-9.

¹H-NMR(CDCl₃)δ:1.61-1.81(1H,m),2.20-2.42(4H,m),2.60-2.78(1H,m),3.12-3.45(2H,m),3.81-3.95(1H,m),4.02-4.25(2H,m),4.37(2B,d,J=6.0Hz),5.12-5.32(4H,m),7.00-7.31(4H,m),7.35-7.60(4H,m),8.11-8.32(4H,m)

REFERENCE EXAMPLE 105

(2R,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2- 3-N-(p-nitrobenzyloxycarbonyl)aminomethyl!benzyl!-pyrrolidine ##STR309##(Step 1)

(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-3-(t-butyldimethylsiloxymethyl)-α-hydroxybenzyl!pyrrolidine (11.3 g,yield: 86.5%) was prepared as a yellow oily substance from(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (7.8 g,23.7 mmol) and 3-(t-butyldimethylsiloxymethyl)bromobenzene (13.7 g, 4.55mmol), in the same manner as in Reference Example 103-1.

¹H-NMR(CDCl₃)δ:0.00-0.16(12H,m),0.78-1.02(18H,m),1.42-2.12(11H,m),3.21-3.90(2H,m),4.08-4.58(2H,m),4.78(2H,s),7.18-7.40(4H,m)

(Step 2)

(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-3-(t-butyldimethylsiloxymethyl)-α-(methylthiothiocarbonyloxy)benzyl!pyrrolidine(9.8 g, yield: 74.6%) was prepared as a yellow oily substance, from thecompound (11.3 g, 20.5 mmol) obtained in Step 1, 60% sodium hydride (1.1g, 27.5 mmol), carbon disulfide (3.5 ml, 58.2 mmol) and methyl iodide(2.45 ml, 39.4 mmol), in the same manner as in Reference Example 104-2.

¹H-NMR(CDCl₃)δ:0.00-0.20(12H,m),0.82-1.10(18H,m),1.50-1.70(10H,m),1.90-2.20(1H,m),2.66(3H,s),4.30-4.68(2H,m),4.81(2H,s),7.10-7.50(4H,m)

(Step 3)

(2R,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-3-(t-butyldimethylsiloxymethyl)benzyl!pyrrolidine (6.53 g, yield: 79.8%)was prepared as a yellow oily substance, from the compound (9.8 g, 15.3mmol) obtained in Step 2 and catalytic amounts of2,2'-azobisisobutyronitrile and tributyltin hydride (27.0 ml, 100.4mmol), in the same manner as in Reference Example 104-3.

¹H-NMR(CDCl₃)δ:0.00-0.15(12H,m),0.80-1.00(18H,m),1.20-1.88(11H,m),2.55-3.40(4H,m),3.92-4.50(2H,m),4.70(2H,s),6.98-7.40(4H,m)

(Step 4)

A solution of the compound (6.5 g, 12.2 mmol) obtained in Step 3 in2.17N hydrogen chloride-methanol (40 ml) was stirred at room temperaturefor 15 hours and then concentrated in vacuo. Dichloromethane was addedto the residue and the volatile components were distilled off in vacuoto give a yellow oily residue containing(2R,4R)-4-hydroxy-2-(hydroxybenzyl)pyrrolidine monohydrochloride, whichwas used for the next reaction without purification.

(Step 5)

A solution of the compound obtained in Step 4 in dioxane-water (1:1, 100ml) was adjusted to pH 9.0 with 1N aqueous sodium hydroxide. While thissolution was maintained at pH 8.0-9.0 by using 1N aqueous sodiumhydroxide, a solution of p-nitrobenzyloxycarbonyl chloride (2.7 g, 13.4mmol) in dioxane (5 ml) was added dropwise thereto. The reactionsolution was poured into a liquid mixture of ethyl acetate-water. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous sodium sulfate, and concentrated in vacuo. The resultingresidue was subjected to silica gel column chromatography (Wakogel™C-300 ethyl acetate) to give(2R,4R)-4-hydroxy-2-(3-hydroxymethylbenzyl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(2.91 g, yield: 61.8%) as a yellow oily substance.

¹H-NMR(CDCl₃)δ:1.60-2.03(2H,m),2.58-2.80(1H,m),3.08-3.65(3H,m),4.22-4.35(2H,brs),4.65(2H,s),5.30(2H,s),6.98-7.30(4H,m),7.55(2H,d,J=8.6Hz),8.19-8.28(2H,m)

(step 6)

(2R,4R)-4-Mesyloxy-2-(3-mesyloxymethylbenzyl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidinewas prepared as a yellow oily substance from the compound (1.21 g, 3.13mmol) obtained in Step 5, mesyl chloride (850 μl, 10.98 mmol) andtriethylamine (1.53 ml, 10.98 mmol), in the same manner as in ReferenceExample 103-6. The product was used for the next reaction withoutpurification.

(Step 7)

(2R,4R)-2-(3-Azidomethylbenzyl)-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(1.38 g, yield: 56.3%) was prepared as a yellow oily substance from thecompound obtained in Step 6 and sodium azide (325 mg, 5.0 mmol) in thesame manner as in Reference Example 103-7.

¹H-NMR(CDCl₃)δ:1.95-2.40(2H,m),2.70-3.45(6H,m),3.89-4.02(1H,m),4.29(2H,s),5.00(1H,brs),5.30(2H,s),7.00-7.35(4H,m),7.56(2H,d,J=8.6Hz),8.25(2H,d,J=8.4Hz)

(Step 8)

(2R,4R)-4-Mesyloxy-N-(p-nitrobenzyloxycarbonyl)-2- 3-N-((p-nitrobenzyloxycarbonyl)aminomethyl!benzyl!-pyrrolidine (1.52 g,containing triphenylphosphine oxide) was prepared as a yellow oilysubstance, from the compound (1.38 g, 2.82 mmol) obtained in Step 7,triphenylphosphine (1.85 g, 7.05 mmol), water (170 μl, 9.4 mmol) andp-nitrobenzyloxycarbonyl chloride (1.04 g, 5.16 mmol), in the samemanner as in Reference Example 103-8.

¹ H-NMR(CDCl₃)δ:1.98-2.40(2H,m),2.72-2.86(1H,m),2.97(3H,s),3.18-3.52(2H,m),4.25-4.40(2H,m),4.85-4.96(1H,m),5.29(2H,s),5.30(2H,s),6.94-7.31(4H,m),8.16-8.30(4H,m)

(Step 9)

(2R,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2- 3-N-(p-nitrobenzyloxycarbonyl)aminomethyl!benzyl!-pyrrolidine (981 mg,yield: 56.1%) was prepared as a red oily substance, from the compound(1.52 g) obtained in Step 8 and potassium thioacetate (480 mg, 4.21mmol), in the same manner as in Reference Example 103-9.

¹H-NMR(CDCl₃)δ:1.60-1.80(1H,m),2.34(3H,s),2.58-2.80(1H,m),3.12-3.50(2H,m),3.80-3.94(1H,m),4.05-4.21(2H,m),4.32-4.42(2H,m),5.08-5.31(5H,m),7.00-7.31(4H,m),7.48-7.60(4H,m),8.18-8.30(4H,m)

REFERENCE EXAMPLE 106

(2R,4S)-4-Acetylthio-2-benzyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidine##STR310## (Step 1)

2.0M Phenylmagnesium bromide-tetrahydrofuran solution (22.8 ml, 45.6mmol) was added dropwise to a solution of(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (10 g, 30.4mmol) in tetrahydrofuran (200 ml) at -78° C. in a nitrogen stream. Thereaction solution was allowed to gradually warm and then stirred at roomtemperature for 3 hours. After addition of water, this reaction solutionwas concentrated in vacuo. The resulting residue was poured into aliquid mixture of ethyl acetate with water. The organic layer was washedwith saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate, and then concentrated in vacuo. The resulting oily residue wassubjected to silica gel column chromatography (Wakogel™ C-300heptane:ethyl acetate 4:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(α-hydroxybenzyl)pyrrolidine(11.98 g, yield: 96.8%) as a colorless oily substance.

¹H-NMR(CDCl₃)δ:0.01(6H,s),0.83(9H,s),1.54(9H,s),1.79-1.92(1H,m),2.83-3.84(3H,m),4.08-4.61(2H,m),4.84-5.34(1H,m),7.34(5H,m)

(Step 2)

(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-(α-methylthiothiocarbonyloxy)benzyl!pyrrolidine (8.58 g, yield: 100%)was prepared as a yellow oily substance from the compound (7.03 g, 17.3mmol) obtained in Step 1, carbon disulfide (3.12 ml, 51.9 mmol), 60%sodium hydride (1.04 g, 26.0 mmol) and methyl iodide (5 ml, 80 mmol), inthe same manner as in Reference Example 104-2.

(Step 3)

(2R,4R)-2-Benzyl-N-t-butoxycarbony-4-(t-butyldimethylsiloxy)pyrrolidine(4.81 g, yield: 71.1%) was prepared as a colorless oily substance fromthe compound (8.58 g, 17.3 mmol) obtained in Step 2, tributyltin hydride(18.6 ml, 69.2 mmol) and α,α'-azobisisobutyronitrile (284 mg, 1.73 mmol)in the same manner as in Reference Example 104-3.

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.83(9H,s),1.52(9H,s),1.81(2H,m),2.73(1H,m),3.06(1H,m),3.29(2H,m), 4.11(2H,m),7.22(5H,m)

(Step 4)

A crude product (1.07 g) of (2R,4R)-2-benzyl-4-hydroxypyrrolidinemonohydrochloride was prepared as a yellow oily substance from thecompound (2.4 g, 6.14 mmol) obtained in Step 3 and 3.7N hydrogenchloride-methanol solution in the same manner as in Reference Example105-4. The crude product was used for the next reaction withoutpurification.

¹ H-NMR(D₂O)δ:1.88-2.19(2H,m),3.04-3.32(3H,m),3.51-3.69(2H,m),4.17(1H,m),7.39(5H,m)

(Step 5)

(2R,4R)-2-Benzyl-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (1.52g, yield: 70.0%) was prepared as a yellow oily substance from the crudeproduct (1.07 g) obtained in Step 4 and p-nitrobenzyloxycarbonylchloride (1.72 g, 8.0 mmol) in the same manner as in Reference Example105-5.

¹ H-NMR(CDCl₃)δ:1.80(2H,m),2.76(1H,m),3.03-3.41(2H,m),3.08(1H,m),4.29(2H,m),5.29(2H,s),7.19(5H,m), 7.52(2H,m),8.23(2H,m)

(Step 6)

A crude product of(2R,4R)-2-benzyl-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(1.84 g) was prepared as a yellow oily substance from the compound (1.52g, 4.27 mmol) obtained in Step 5, triethylamine (655 μl, 4.70 mmol) andmesyl chloride (364 μl, 4.70 mmol) in the same manner as in ReferenceExample 104-9. The crude product was used for the next reaction withoutpurification.

¹ H-NMR(CDCl₃)δ:2.02(1H,m),2.22(1H,m),2.83(1H,m),2.97(3H,s),3.13(1H,m),3.40(1H,m),3.94(1H,m),4.33(1H,m),4.97(1H,m),5.28(2H,s),7.10(2H,m),7.26(3H,m),7.52(2H,m),8.23(2H,m)

(Step 7)

The title compound (1.02 g, yield: 57.8%) was prepared as a brown oilysubstance from the crude product (2.06 g, 4.23 mmol) obtained in Step 6and potassium thioacetate (1.45 g, 12.7 mmol) in the same manner as inReference Example 103-9.

¹ H-NMR(CDCl₃)δ:1.73(1H,m),2.31(3H,s),2.36(1H,m),2.69(1H,m),3.28(2H,m),3.88(1H,m),4.11(2H,m),5.26(2H,m),7.21(5H,m),7.51(2H,m),8.23(2H,m)

REFERENCE EXAMPLE 107

(2R,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-4-(p-nitrobenzyloxycarbonylaminomethyl)-1-naphthylmethyl!pyrrolidine##STR311## (Step 1)

A solution of 4-hydroxymethyl-1-bromonaphthalene (3 g, 12.7 mmol) intetrahydrofuran (50 ml) was added dropwise to a solution of 1.6M butyllithium-hexane solution (20.6 ml, 32.9 mmol) in tetrahydrofuran (100 ml)at -72° C. in a nitrogen stream over 30 minutes. The resulting reactionsolution was stirred at -72° C. for 30 minutes and a solution of(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (4.17 g,12.7 mmol) in tetrahydrofuran (50 ml) was added dropwise over 10minutes. Then, the reaction solution was stirred at -63° C. for 10minutes. After addition of saturated aqueous ammonium chloride, thereaction solution was concentrated in vacuo. The resulting residue waspoured into a liquid mixture of ethyl acetate with water. The organiclayer was washed with saturated aqueous sodium chloride, dried overanhydrous sodium sulfate, and concentrated in vacuo. The resulting oilyresidue was subjected to silica gel column chromatography (Wakogel™C-300 heptane-ethyl acetate 3:1→2:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-hydroxy(4-hydroxymethyl-1-naphthyl)methyl!pyrrolidine (2.71 g, yield:44.0%) as a colorless oily substance.

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.79(9H,s),1.54(9H,s),2.01(2H,m),3.26-3.52(2H,m),4.03-4.68(2H,m),5.03-5.36(2H,m),5.94-6.29(1H,m),7.52(4H,m),8.09(1H,m),8.38(1H,m)

(Step 2)

To a solution of the compound (1.15 g, 2.37 mmol) obtained in Step 1 inN,N-dimethylformamide (20 ml), imidazole (193 mg, 2.84 mmol) andt-butyldimethylsilyl chloride (393 mg, 2.61 mmol) were added and theresulting reaction solution was stirred at room temperature for 2 hours.The reaction solution was poured into a liquid mixture of ethyl acetatewith water. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate and concentrated in vacuoto give a crude product of(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-t-butyldimethylsiloxymethyl-1-naphthyl)hydroxymethyl!pyrrolidine as ayellow oily substance (1.45 g), which was used for the next reactionwithout purification.

(Step 3)

60% Sodium hydride (142 mg, 3.56 mmol) was added to a solution of thecrude product (1.45 g) obtained in Step 2 in tetrahydrofuran (30 ml).The resulting reaction solution was stirred at room temperature for 30minutes and carbon disulfide (427 μl, 7.11 mmol) was added thereto. Thereaction solution was stirred at the same temperature for 30 minutes.Methyl iodide (5 ml, 80.3 mmol) was added to the reaction solution atroom temperature. The reaction solution was poured into a liquid mixtureof ethyl acetate with water. The organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The resulting oily residue was subjected tosilica gel column chromatography (Wakogel™ C-300 heptane-ethyl acetate10:1) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-t-butyldimethylsiloxymethyl-1-naphthyl)(methylthiothiocarbonyloxy)methyl!pyrrolidine(1.19 g, yield: 72.4%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ:0.01(6H,m),0.13(6H,s),0.81(9H,m),0.96(9H,s),1.40(9H,m),2.00(1H,m),2.30(1H,m),2.58(3H,s),2.80-3.13(1H,m),3.28-3.60(1H,m),3.74-4.01(1H,m),4.51-4.88(2H,m),5.18(2H,m),7.52(4H,m),7.84-8.36(2H,m)

(Step 4)

To a solution of the compound (1.19 g, 1.71 mmol) obtained in Step 3 intoluene (30 ml), tributyltin hydride (1.84 ml, 6.84 mmol) andα,α'-azobisisobutyronitrile (28 mg, 0.17 mmol) were added in a nitrogenstream. The resulting reaction solution was refluxed under heating for16 hours and then poured into saturated aqueous potassium fluoride. Theprecipitate was filtered off and the filtrate was poured into a liquidmixture of ethyl acetate with water. The organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and concentrated in vacuo. The resulting oily residue was subjected tosilica gel column chromatography (Wakogel™ C-300 heptane:ethyl acetate10:1) to give(2R,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-t-butyldimethylsiloxymethyl-1-naphthylmethyl)pyrrolidine(924 g, yield: 92.4%) as a colorless oily substance.

¹ H-NMR(CDCl₃)δ:0.01(6H,m),0.12(6H,s),0.81(9H,s),0.96(9H,s),1.54(9H,s),1.68(1H,m),1.85(1H,m),2.82(1H,m),3.19-3.52(2H,m),3.80(1H,m),4.09-4.42(2H,m),5.19(2H,s),7.22(1H,m),7.51(3H,m),7.99(1H,m),8.23-8.46(1H,m)

(Step 5)

A solution of the compound (906 mg, 1.55 mmol) obtained in Step 4 in2.7N hydrogen chloride-dioxane (30 ml) was stirred at room temperaturefor 49 hours. This reaction solution was concentrated in vacuo to give acrude product of(2R,4R)-4-hydroxy-2-(4-hydroxymethyl-1-naphthylmethyl)pyrrolidinehydrochloride, which was used for the next reaction withoutpurification.

(Step 6)

A solution of the crude product obtained in Step 5 in a mixture ofdioxane-water (4:1, 50 ml) was adjusted to pH 10.0 with 1N aqueoussodium hydroxide. While this solution was maintained at pH 8.0-10.0 byusing 1N aqueous sodium hydroxide, a solution ofp-nitrobenzyloxycarbonyl chloride (434 mg, 2.01 mmol) in dioxane (2 ml)was added dropwise thereto under cooling with ice. This reactionsolution was poured into a liquid mixture of ethyl acetate with water.The organic layer was washed with saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresulting oily residue was subjected to silica gel column chromatography(Wakogel™ C-300 heptane-ethyl acetate 1:4) to give(2R,4R)-4-hydroxy-2-(4-hydroxymethyl-1-naphthylmethyl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(191 mg, yield: 28.3%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ:1.81(1H,m),1.93(1H,m),2.73(1H,m),3.61(1H,m),3.75(1H,m),4.03-4.52(2H,m),5.08-5.36(3H,m),7.20-7.64(5H,m),7.99-8.53(3H,m)

(Step 7)

To a solution of the compound (191 mg, 0.44 mmol) obtained in Step 6 indichloromethane (5 ml), triethylamine (244 μl, 1.75 mmol) and mesylchloride (85 μl, 1.10 mmol) were successively added in a nitrogen streamunder cooling with ice and the resulting reaction solution was stirredat the same temperature for 10 minutes. The reaction solution was pouredinto a liquid mixture of ethyl acetate with water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and concentrated in vacuo to give a crude product of(2R,4R)-4-mesyloxy-2-(4-mesyloxymethyl-1-naphthylmethyl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidineas a yellow oily substance, which was used for the next reaction withoutpurification.

(Step 8)

To a solution of the crude product obtained in Step 7 inN,N-dimethylformamide (5 ml), sodium azide (57 mg, 0.88 mmol) was addedand the resulting reaction solution was stirred at room temperature for2 hours. It was poured into a liquid mixture of ethyl acetate withwater. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, and concentrated in vacuoto give a crude product of(2R,4R)-2-(4-azidomethyl-1-naphthylmethyl)-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidineas a yellow oily substance, which was used for the next reaction withoutpurification.

¹ H-NMR(CDCl₃)δ:2.12(2H,m),2.79(1H,m),3.61-3.90(1H,m),4.01-4.12(1H,m),4.23(1H,m),4.50(1H,m),4.66(1H,m),5.13-5.36(2H,m),7.20-7.71(5H,m),8.03(2H,m),8.20-8.51(3H,m)

(Step 9)

To a solution of the crude product (341 mg) obtained in Step 8 intetrahydrofuran (10 ml), triphenylphosphine (392 mg, 1.50 mmol) andwater (3 ml) were successively added. After 23 hours of stirring at roomtemperature, the reaction solution was concentrated in vacuo. Theresulting residue was dissolved in dichloromethane (10 ml) andp-nitrobenzyloxycarbonyl chloride (242 mg, 1.12 mmol) anddiisopropylethylamine (391 μl, 2.25 mmol) were successively addedthereto. The reaction solution was stirred at room temperature for 10minutes and then concentrated in vacuo. The resulting residue was pouredinto a liquid mixture of ethyl acetate with water. The organic layer waswashed successively with saturated aqueous ammonium chloride andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and concentrated in vacuo. The resulting oily residue was subjected tosilica gel column chromatography (Wakogel™ C-300 heptane-ethyl acetate2:3) to give (2R,4R)-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)-2-4-(p-nitrobenzyloxycarbonylaminomethyl)-1-naphthylmethyl!pyrrolidine(493 mg) containing triphenylphosphine oxide as a yellow oily substance.

(Step 10)

To a solution of the mixture (493 mg) obtained in Step 1 inN,N-dimethylformamide (10 ml), potassium thioacetate (343 mg, 3.0 mmol)was added. The resulting reaction solution was refluxed under heatingfor 3 hours and then poured into a liquid mixture of ethyl acetate withwater. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, and concentrated invacuo. The resulting oily residue was subjected to silica gel columnchromatography (Wakogel™ C-300 heptane-ethyl acetate 1:1) to give thetitle compound (14.4 mg) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ:1.81(1H,m),2.16(1H,m),2.83(1H,m),3.42(1H,m),3.90(1H,m),4.09-4.28(2H,m),4.36(1H,m),4.73(2H,m),5.16(1H,m),5.24(2H,m),5.31(2H,m),7.31(1H,m),7.55(6H,m),8.01(2H,m),8.23(4H,m), 8.56(1H,m)

REFERENCE EXAMPLE 108

(2R,4S)-4-Acetylthio-N-allyloxycarbonyl-2-(1-naphthylmethyl)pyrrolidine##STR312## (Step 1)

Magnesium (3.4 g, 140 mmol) and a solution of 1,2-dibromoethane (5.3 ml,60.8 mmol) in diethyl ether (40 ml) were successively added to asolution of 1-bromonaphthalene (12.6 g, 60.8 mmol) in diethyl ether (160ml) at room temperature in a nitrogen stream and the resulting reactionsolution was refluxed under heating for 3 hours. The reaction solutionwas gradually cooled and a solution of(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsilyl)prolinal (10 g, 30.4mmol) in tetrahydrofuran (40 ml) was added dropwise thereto undercooling with ice over 10 minutes. The reaction solution was stirred atthe same temperature for 10 minutes. After addition of saturated aqueousammonium chloride, the reaction solution was concentrated in vacuo. Theresulting residue was poured into a liquid mixture of ethyl acetate withwater. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, and concentrated invacuo. The resulting oily residue was subjected to silica gel columnchromatography (Wakogel™ C-300 heptane:ethyl acetate 500:1→5:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-hydroxy(1-naphthyl)methyl!pyrrolidine (12.36 g, yield: 89%) as a yellowoily substance.

¹ -NMR(CDCl₃)δ:0.01(6H,s),0.80(9H,s),1.55(9H,s),1.60(1H,m),2.08(1H,m),3.20-3.78(2H,m),4.03-4.71(2H,m),6.08(1H,m),7.49(3H,m),7.81(3H,m),8.29(1H,m)

(Step 2)

(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-(methylthiothiocarbonyloxy)(1-naphthyl)methyl!pyrrolidine was preparedas a yellow oily substance (5.18 g, yield: 52.2%) from the compound(8.29 g, 18.2 mmol) obtained in Step 1, carbon disulfide (3.27 ml, 54.5mmol), 60% sodium hydride (1.09 g, 27.2 mmol) and methyl iodide (10 ml,159 mmol), in the same manner as in Reference Example 107-3.

(Step 3)

(2R,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(1-naphthylmethyl)pyrrolidine(4.2 g, yield: 100%) was prepared as a pale yellow oily substance fromthe compound (5.18 g, 9.47 mmol) obtained in Step 2, tributyltin hydride(19.5 ml, 72.6 mmol) and α,α'-azobisisobutyronitrile (156 mg, 0.95mmol), in the same manner as in Reference Example 107-4.

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.80(9H,s),1.53(9H,s),1.61(1H,m),1.83(1H,m),2.83(1H,m),3.14-3.60(2H,m),3.79(1H,m),4.03-4.46(2H,m),7.36(1H,m),7.40(3H,m),7.80(2H,m),8.31(1H,m)

(Step 4)

A brown powder containing(2R,4R)-4-hydroxy-2-(1-naphthylmethyl)pyrrolidine monohydrochloride wasprepared from the compound (4.23 g, 9.60 mmol) obtained in Step 3 and 2Nhydrogen chloride-dioxane solution (100 ml) in the same manner as inReference Example 107-5.

¹ H-NMR(D₂ O)δ:1.73-2.08(2H,m),3.02-3.29(2H,m),3.49(2H,m),4.08-4.52(2H,m),7.43(4H,m), 7.80(2H,m),8.03(1H,m)

(Step 5)

To a suspension of the crude product obtained in Step 4 indichloromethane (50 ml), triethylamine (6.7 ml, 48.0 mmol) andallyloxycarbonyl chloride (2.04 ml, 19.2 mmol) were successively addedand the resulting reaction solution was stirred at room temperature for10 minutes. The reaction solution was concentrated in vacuo and theresulting residue was poured into a liquid mixture of ethyl acetate withwater. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate and concentrated in vacuoto give a crude product of(2R,4R)-N-allyloxycarbonyl-4-hydroxy-2-(1-naphthylmethyl)pyrrolidine(3.16 g) as a yellow oily substance, which was used for the nextreaction without purification.

¹ H-NMR(CDCl₃)δ:1.96(1H,m),2.74(2H,m),3.56(2H,m),4.06(1H,m),4.40(2H,m),4.70(2H,m),5.31(2H,m),6.02(1H,m),7.40(4H,m),7.79(2H,m),8.18-8.51(1H,m)

(Step 6)

(2R,4R)-N-Allyloxycarbonyl-4-mesyloxy-2-(1-naphthylmethyl)pyrrolidine(1.61 g) was prepared as a pale yellow oily substance from the crudeproduct (3.16 g) obtained in Step 5, triethylamine (1.48 ml, 10.6 mmol)and mesyl chloride (820 μl, 10.6 mmol), in the same manner as inReference Example 107-7.

¹ H-NMR(CDCl₃)δ:2.09(1H,m),2.74(1H,m),2.92(3H,s),3.61(1H,m),3.87-4.28(3H,m),4.47(1H,m),4.73(2H,m),5.13(1H,m),5.21-5.51(2H,m),6.01(1H,m),7.38(4H,m),7.76(2H,m),8.12-8.47(1H,m)

(Step 7)

The title compound (1.15 g, yield: 75.0%) was prepared as a yellow solidfrom the compound (1.61 g, 3.83 mmol) obtained in Step 6 and potassiumthioacetate (1.31 g, 11.5 mmol), in the same manner as in ReferenceExample 107-10.

¹ H-NMR(CDCl₃)δ:1.73(1H,m),2.16(1H,m),2.38(3H,s),2.83(1H,m),3.40(1H,m),3.91(1H,m),4.03-4.42(3H,m),4.73(2H,m),5.19-5.52(2H,m),6.01(1H,m),7.41(4H,m),7.73(2H,m),8.19-8.56(1H,m)

REFERENCE EXAMPLE 109

(2R,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-4'-(p-nitrobenzyloxycarbonylaminomethyl)-4-biphenylmethyl!pyrrolidine##STR313## (Step 1)

A solution of p-bromoiodobenzene (9.44 g, 33.4 mmol) in tetrahydrofuran(10 ml) was added dropwise to a solution of 1.6M butyl lithium-hexanesolution (19.0 ml, 30.3 mmol) in tetrahydrofuran (50 ml) at -78° C. in anitrogen stream over 15 minutes. The resulting reaction solution wasstirred at -78° C. for 40 minutes and then a solution of(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (5.0 g,15.2 mmol) in tetrahydrofuran (17 ml) was added dropwise thereto over 10minutes. The reaction solution was stirred at -78° C. for 1.5 hours.After addition of saturated aqueous ammonium chloride, the reactionsolution was poured into a liquid mixture of ethyl acetate with water.The organic layer was washed with saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresulting oily residue was subjected to silica gel Column chromatography(Wakogel™ C-300, 200 ml ethyl acetate-heptane 2:3→3:2) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-bromophenyl)hydroxymethyl!pyrrolidine (6.30 g, yield: 85.3%) as apale yellow oily substance.

¹H-NMR(CDCl₃)δ:0.01(6H,s),0.85(9H,s),1.52(9H,s),1.76-2.08(2H,m),2.86-6.15(5H,m),7.28-7.58(4H,m)

(Step 2)

To a solution of the compound (4.46 g, 9.17 mmol) obtained in Step 1 in1,2-dimethoxyethane (40 ml), tetrakistriphenylphosphine palladium (508.5mg, 4.8 mol %) was added and the resulting reaction solution was stirredat 15 minutes. To the reaction solution, a solution of 4-t-butyldiphenylsiloxymethyl!phenyl borate (4.12 g, 10.5 mmol; see U.S.Pat. No. 5,192,758) in ethanol-1,2-dimethoxyethane (1:1, 30 ml) wasadded. This reaction solution was stirred at 15 minutes. After additionof 2M aqueous potassium carbonate (40 ml), the reaction solution wasstirred at 110° C. in a nitrogen stream for 19 hours and then was pouredinto a liquid mixture of ethyl acetate with water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and concentrated in vacuo. The resulting oily residuewas subjected to silica gel column chromatography (Wakogel™ C-300 200 mlethyl acetate-heptane 2:3→3:2) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-4'-(t-butyldiphenylsiloxymethyl)-4-biphenyl!hydroxymethyl!pyrrolidine(5.42 g, yield: 78.5%) as a pale yellow oily substance.

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.84(9H,s),1.11(9H,s),1.58(9H,s),1.82-1.95(2H,m),2.89-5.99(7H,m),7.34-7.75(18H,m)

(Step 3)

(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-4'-(t-butyldiphenylsiloxymethyl)-4-biphenyl!(methylthiothiocarbonyloxy)methyl!pyrrolidinewas prepared as a pale yellow oily substance (1.02 g, yield: 91.1%) fromthe compound (1.0 g, 1.33 mmol) obtained in Step 2, sodium hydride (79.8mg, 1.99 mmol), carbon disulfide (0.24 ml, 3.99 mmol) and methyl iodide(0.83 ml, 13.3 mmol), in the same manner as in Reference Example 107-3.

¹ H-NMR(CDCl₃)δ:0.09(6H,s),0.80-0.89(9H,m),1.13(9H,s),1.51-1.54(9H,m),1.75-2.36(4H,m),2.62(3H,s),3.05-3.83(2H,m),4.30-4.63(1H,m),4.72(2H,s),6.86-7.76(18H,m)

(Step 4)

(2R,4R)-2-4'-(t-Butyldiphenylsiloxymethyl)-4-biphenylmethyl!-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)pyrrolidinewas prepared as a pale yellow oily substance (894 mg, yield: 100%) fromthe compound (1.0 g, 1.19 mmol) obtained in Step 3, tributyltin hydride(2.56 ml, 9.5 mmol) and 2,2'-azobisisobutyronitrile (20 mg), in the samemanner as in Reference Example 107-4.

¹ H-NMR(CDCl₃)δ:0.03(6H,s),0.82(9H,s),1.11(9H,s),1.52(9H,s),1.84-1.88(2H,m),2.71-3.41(4H,m),4.02-4.27(1H,m),4.78-4.82(3H,m),7.22-7.76(18H,m)

(Step 5)

A crude product of(2R,4R)-4-hydroxy-2-(4'-hydroxymethyl-4-biphenylmethyl)pyrrolidinemonohydrochloride was prepared as a yellow oily residue from thecompound (874 mg, 1.19 mmol) obtained in Step 4 and 1.75N hydrogenchloride-methanol solution (30 ml), in the same manner as in ReferenceExample 107-5.

(Step 6)

(2R,4R)-4-Hydroxy-2-(4'-hydroxymethyl-4-biphenylmethyl)-N-(p-nitrobenzyloxycarbony)pyrrolidinewas prepared as a pale yellow oily substance (401 mg, yield: 73.0%) fromthe compound obtained in Step 5, p-nitrobenzyloxycarbonyl chloride(307.2 mg, 1.42 mmol) and sodium hydrogencarbonate (1.0 g, 11.8 mmol),in the same manner as in Example 107-6.

¹H-NMR(CDCl₃)δ:1.68-1.99(2H,m),2.76-3.68(4H,m),4.28-4.41(2H,m),4.75-4.77(2H,m),5.29(2H,s),7.15-7.58(10H,m),8.20-8.24(2H,m)

(Step 7)

A crude product of(2R,4R)-4-mesyloxy-2-(4'-mesyloxymethyl-4-biphenylmethyl)-N-(p-nitrobenzyloxcarbonyl)pyrrolidinewas prepared as a yellow oily residue from the compound (485 mg, 1.05mmol) obtained in Step 6, mesyl chloride (0.20 ml, 2.62 mmol) andtriethylamine (0.44 ml, 3.15 mmol), in the same manner as in ReferenceExample 107-7.

(Step 8)

(2R,4R)-2-(4'-Azidomethyl-4-biphenylmethyl)-4-mesyloxy-N-(p-nitrobenzyloxycarbony)pyrrolidinewas prepared as a pale yellow oily substance (573 mg, yield: 96.6%) fromthe residue obtained in Step 7 and sodium azide (136.3 mg, 2.10 mmol),in the same manner as in Reference Example 107-8.

¹ H-NMR(CDCl₃)δ:2.09-2.41(2H,m),2.81-3.50(4H,m),2.99(3H,s),3.93-4.41(3H,m),5.04(1H,s),5.31(2H,s),7.13-7.60(10H,m),8.22-8.29(2H,m)

(Step 9)

(2R,4R)-4-Mesyloxy-N-(p-nitrobenzyloxycarbony)-2-4'-(p-nitrobenzyloxycarbonylaminomethyl)-4-biphenylmethyl!pyrrolidinewas prepared as a pale yellow oily substance (557 mg, yield: 77.6%) fromthe compound (565 mg, 1.00 mmol) obtained in Step 8, triphenylphosphine(471.6 mg, 1.80 mmol), p-nitrobenzyloxycarbonyl chloride (247.7 mg, 1.15mmol) and triethylamine (0.18 ml, 1.30 mmol), in the same manner as inReference Example 107-9.

¹ H-NMR(CDCl₃)δ:2.07-2.43(2H,m),2.84-2.95(1H,m),2.99(3H,s),3.08-3.50(2H,m),3.95-4.48(4H,m),5.04-5.33(5H,m),7.12-7.58(12H,m),8.21-8.26(4H,m)

(Step 10)

(2R,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-4'-(p-nitrobenzyloxycarbonylaminomethyl)-4-biphenylmethyl!pyrrolidinewas prepared as a pale yellow oily substance (483 mg, yield: 90.3%) fromthe compound (550 mg, 0.77 mmol) obtained in Step 9 and potassiumthioacetate (262.2 mg, 2.30 mmol), in the same manner as in ReferenceExample 107-10.

¹H-NMR(CDCl₃)δ:1.71-2.22(2H,m),2.35(3H,s),2.68-3.29(4H,m),3.41-3.96(2H,m),4.10-4.47(3H,m),5.16-5.27(5H,m),7.16-7.63(12H,m),8.19-8.24(4H,m)

In the following Reference Example 110, physicochemical data ofcompounds used in Examples as thiols or thiol precursors are shown.

REFERENCE EXAMPLE 110 ##STR314## Diastereomer A

¹ H-NMR(CDCl₃)δ:1.86(1H,m),2.30(3H,s),2.80(1H,m),3.42(1H,dd,J=11&8.5Hz),3.97(1H,m),4.20-4.65(7H,m), 7.15-7.30(4H,m)

MS:419(M+H)

Diastereomer B

¹ H-NMR(CDCl₃)δ:2.25(1H,m),2.32(3H,s),3.62(1H,m),4.06(2H,m),4.34(2H,m),4.40-4.70(4H,m),4.85-5.40(6H,m),7.20-7.40(2H,m)

MS:419(M+H)

REFERENCE EXAMPLE 111

(2S,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2- hydroxy 4'-(p-nitrobenzyloxycarbonylamino)methyl!-4-biphenyl!methyl!pyrrolidinediastereomer I ##STR315## (Step 1)

A solution of 4-bromo-1-iodobenzene (9.44 g, 33.4 mmol) intetrahydrofuran (10 ml) was added dropwise to a solution of 1.6M n-butyllithium-hexane solution (19.0 ml, 30.3 mmol) in tetrahydrofuran (50 ml)at -78° C. for in a nitrogen stream over 15 minutes. This reactionsolution was stirred -78° C. for 40 minutes and then a solution of(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (5.0 g,15.2 mmol) in tetrahydrofuran (17 ml) was added dropwise thereto over 10minutes. The reaction solution was stirred at -78° C. for 1.5 hours andthen saturated ammonium chloride solution was added thereto. Thereaction solution was poured into a liquid mixture of ethyl acetate withwater. The organic layer was washed with saturated aqueous sodiumchloride and dried over anhydrous sodium sulfate. The solvent wasdistilled off in vacuo and the resulting oily residue was subjected tosilica gel column chromatography (Wakogel™ C-300, 200 ml; ethylacetate-heptane 2:3→3:2) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(4-bromophenyl)hydroxymethyl!pyrrolidine (6.30 g, yield: 85.3%) as apale yellow oily substance.

¹H-NMR(CDCl₃)δ:0.01(6H,s),0.85(9H,s),1.52(9H,s),1.76-2.08(2H,m),2.86-6.15(5H,m),7.28-7.58(4H,m)

(Step 2)

To a solution of the compound (4.46 g, 9.17 mmol) obtained in Step 1 in1,2-dimethoxyethane (40 ml), tetrakistriphenylphosphinepalladium (0)(508.5 mg, 4.8 mol %) was added at room temperature and the reactionsolution was stirred for 15 minutes. To the reaction solution, asolution of 4-(t-butyldiphenylsiloxymethyl)phenyl borate (4.12 g, 10.5mmol; see U.S. Pat. No. 5,192,758) in ethanol-1,2-dimethoxyethane (1:1,30 ml) was added. The reaction solution was stirred for 15 minutes and2M aqueous potassium carbonate (40 ml) was added thereto. The reactionsolution was stirred at 110° C. in a nitrogen stream for 19 hours andthen poured into a liquid mixture of ethyl acetate with water. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous sodium sulfate, and concentrated in vacuo. The resultingoily residue was subjected to silica gel column chromatography (Wakogel™C-300, 200 ml; ethyl acetate-heptane=2:3→3:2) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-4'-(t-butyldiphenylsiloxymethyl)-4-biphenyl!hydroxymethyl!pyrrolidine(5.42 g, yield: 78.5%) as a pale yellow oily substance.

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.84(9H,s),1.11(9H,s),1.58(9H,s),1.82-1.95(2H,m),2.89-5.99(7H,m),7.34-7.75(18H,m)

(Step 3)

To a solution of the compound (2.50, 3.32 mmol) obtained in Step 2 indichloromethane (30 ml), 4-N,N-dimethylaminopyridine (609 mg, 5.00 mmol)and acetic anhydride (0.38 ml, 4.00 mmol) were successively added in anitrogen stream under cooling with ice and the resulting reactionsolution was stirred at the same temperature for 10 minutes. It wasallowed to gradually warm and then stirred at room temperature for 1.5hours and aqueous sodium hydrogencarbonate was added thereto. Thereaction solution was poured into a liquid mixture of ethyl acetate withwater. The organic layer was washed with saturated aqueous sodiumchloride and dried over anhydrous sodium sulfate. The solvent wasdistilled off in vacuo and the resulting oily residue was subjectedsilica gel column chromatography (Wakogel™ C-300, 100 ml; ethylacetate-heptane=3:17→1:4) to give (2S,4R)-2- acetoxy4'-(t-butyldiphenylsiloxymethyl)-4-biphenyl!methyl!-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)pyrrolidinediastereomer I as a pale yellow substance (polar compound, 1.09 g,yield: 41.3%) and diastereomer II as a pale yellow oily substance (lesspolar compound, 1.38 g, yield: 52.3%).

Diastereomer I

¹ H-NMR(CDCl₃)δ:0.04(6H,s),0.95(9H,s),1.11(9H,s),1.57(9H,s),1.65-1.76(1H,m),2.16(3H,s),2.18-2.24(1H,m),3.33-3.56(2H,m),4.27-4.50(2H,m),4.81(2H,s),6.38(1H,s),7.27-7.72(18H,m)

Diastereomer II

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.80(9H,s),1.15(9H,s),1.59(9H,s),1.81-2.11(2H,m),2.16-2.20(3H,m),3.05-3.71(3H,m),4.31-4.45(1H,m),4.86(2H,s),6.12-6.23(1H,m),7.32-7.85(18H,m)

(Step 4)

To a solution of the compound (diastereomer I: 740 mg, 0.93 mmol)obtained in Step 3 in tetrahydrofuran (13 ml), acetic acid (43 μl, 0.75mmol) and 1.0M tetrabutylammonium fluoride-tetrahydrofuran solution(3.72 ml, 3.72 mmol) were successively added under cooling with ice. Theresulting reaction solution was stirred at the same temperature for 15minutes and then at 35° C. for 4 hours. The reaction solution was pouredinto a liquid mixture of ethyl acetate with water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and concentrated in vacuo. The resulting oily residuewas subjected to silica gel column chromatography (Wakogel™ C-300, 100mg; ethyl acetate-heptane=9:1) to give (2S,4R)-2-acetoxy(4'-hydroxymethyl-4-biphenyl)methyl!-N-t-butoxycarbonyl-4-hydroxypyrrolidinediastereomer I as a pale yellow oily substance (polar compound, 420 mg,yield: 99.9%). Likewise, from the compound (diastereomer II: 1.06 g,1.33 mmol), acetic acid (0.06 ml, 1.07 mmol) and 1.0M tetrabutylammoniumfluoride-tetrahydrofuran solution (5.34 ml, 5.34 mmol), (2S,4R)-2-acetoxy(4'-hydroxymethyl-4-biphenyl)methyl!-N-t-butoxycarbonyl-4-hydroxypyrrolidinediastereomer II was prepared as a pale yellow substance (less polarcompound, 593 mg, yield: 99.8%).

Diastereomer I

¹ H-NMR(CDCl₃)δ:1.58(9H,s),1.72-2.37(2H,m),2.18(3H,s),3.43-4.52(4H,m),4.74-4.79(2H,m),6.49(1H,s),7.32-7.60(8H,m)

Diastereomer II

¹ H-NMR(CDCl₃)δ:1.55(9H,s),1.68-2.09(2H,m),2.15(3H,s),2.99-4.44(4H,m),4.75(2H,s),6.21(1H,s),7.31-7.60(8H,m)

(Step 5)

To a solution of the compound (diastereomer I: 420 mg, 1.01 mmol)obtained in Step 4 in dichloromethane (15 ml), trifluoroacetic acid (10ml) was added on an ice bath. The resulting reaction solution wasstirred for 45 minutes and then concentrated in vacuo. To a solution ofthe residue in dioxane-water (4:3, 45 ml), sodium hydrogencarbonate (845mg, 10.1 mmol) and p-nitrobenzyloxycarbonyl chloride (249.4 mg, 1.16mmol) were successively added on an ice bath. The resulting reactionsolution was stirred at the same temperature for 10 minutes. Thereaction solution was allowed to gradually warm and stirred at roomtemperature for 1 hour. The reaction solution was poured into a liquidmixture of ethyl acetate with water. The organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and concentrated in vacuo. The resulting oily residue was subjected tosilica gel column chromatography (Wakogel™ C-300,100 ml; acetone-ethylacetate=1:1) to give (2S,4R)-2-acetoxy-4'-hydroxymethyl-4-biphenyl)methyl!-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidinediastereomer I as a pale yellow oily substance (highly polar compound,433 mg, yield: 81.4%). Likewise, from the compound (diastereomer II: 593mg, 1.42 mmol) obtained in Step 4, sodium hydrogencarbonate (1.19 g,14.2 mmol) and p-nitrobenzyloxycarbonyl chloride (352.1 mg, 1.63 mmol),(2S,4R)-2-acetoxy-(4'-hydroxymethyl)-4-biphenyl!methyl!-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidinediastereomer II was prepared as a pale yellow oily substance (slightlypolar compound, 612 mg, yield: 81.5%).

Diastereomer I

¹H-NMR(CDCl₃)δ:1.74-2.39(2H,m),2.16(3H,s),3.38-4.53(4H,m),4.72-4.76(2H,m),5.30(2H,s),6.45-6.53(1H,m),7.39-8.27(12H,m)

Diastereomer II

¹H-NMR(CDCl₃)δ:1.79-2.18(2H,m),2.10(3H,s),3.01-4.62(4H,m),4.72-4.77(2H,m),5.27-5.31(2H,m),6.17-6.20(1H,m),7.30-8.26(12H,m)

(Step 6)

To a solution of the compound (diastereomer I: 433 mg, 0.82 mmol)obtained in Step 5 in dichloromethane-N,N-dimethylformamide (10:3, 13ml), triethylamine (0.34 ml, 2.46 mmol) and mesyl chloride (0.16 ml,2.05 mmol) were added successively in a nitrogen stream under coolingwith ice and the resulting reaction solution was stirred at the sametemperature for 15 minutes. Aqueous sodium hydrogencarbonate was addedto the reaction solution and the organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, andconcentrated in vacuo to give a crude product of (2S,4R)-2-acetoxy(4'-mesyloxymethyl-4-biphenyl)methyl!-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidinediastereomer I as a yellow oily residue, which was used for the nextreaction without purification.

(Step 7)

To a solution of the compound (diastereomer I) obtained in Step 6 inN,N-dimethylformamide (11 ml), sodium azide (106.5 mg, 1.64 mmol) wasadded in a nitrogen stream under cooling with ice and the resultingreaction solution was stirred at the same temperature for 1 hour. Thereaction solution was poured into a liquid mixture of ethyl acetate withwater. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, and concentrated in vacuoto give a crude product of (2S,4R)-2-acetoxy(4'-azidomethyl-4-biphenyl)methyl!-4-mexyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidinediastereomer I as a yellow oily residue, which was used for the nextreaction without purification.

(Step 8)

To a solution of the compound (diastereomer I) obtained in Step 7 indichloromethane-methanol (1:1, 30 ml), 0.2M aqueous potassium carbonate(10 ml) was added under cooling with ice and this reaction solution wasstirred at the same temperature for 20 minutes. The reaction solutionwas allowed to gradually warm and then stirred at room temperature for 1hour. The reaction solution was poured into a liquid mixture of ethylacetate with water. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, and concentratedin vacuo. The resulting oily residue was subjected to silica gel columnchromatography (Wakogel™ C-300, 100 ml; ethyl acetate-heptane=4:1) togive (2S,4R)-2-(4'-azidomethyl-4-biphenyl)hydroxymethyl!-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidinediastereomer I as a pale yellow oily residue (423 mg, yield: 88.8%).

¹H-NMR(CDCl₃)δ:2.28-3.02(2H,m),2.99(3H,s),3.42-4.41(5H,m),5.20-5.42(4H,m),7.38-8.29(12H,m)

(Step 9)

To a solution of the compound (diastereomer I; 418 mg, 0.72 mmol)obtained in Step 8 in tetrahydrofuran-water (2.4:1, 17 ml),triphenylphosphine (339.3 mg, 1.29 mmol) was added at room temperatureand this reaction solution was stirred for 18 hours. To the reactionsolution, triethylamine (0.13 ml, 0.93 mmol) andp-nitrobenzyloxycarbonyl chloride (178.2 mg, 0.83 mmol) weresuccessively added under cooling with ice and the reaction solution wasstirred at the same temperature for 10 minutes. The reaction solutionwas allowed to gradually warm and then stirred at room temperature for 1hours. The reaction solution was poured into a liquid mixture of ethylacetate with water. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, and concentratedin vacuo. The resulting oily residue was subjected to silica gel columnchromatography (Wakogel™ C-300, 60 ml; ethyl acetate-heptane=4:1) togive (2S,4R)-2- hydroxy 4'-(p-nitrobenzyloxycarbonylamino)methyl!-4-biphenyl!methyl!-4-mesyloxy-N-p-nitrobenzyloxycarbonyl)pyrrolidinediastereomer I as a pale yellow oily substance (495 mg, yield: 93.7%).

¹H-NMR(CDCl₃)δ:2.17-3.04(2H,m),3.00(3H,s),3.42-4.46(5H,m),5.21-5.39(7H,m),7.35-8.28(16H,m)

(Step 10)

To a solution of the compound (diastereomer I: 490 mg, 0.67 mmol)obtained in Step 9 in N,N-dimethylformamide (20 ml), potassiumthioacetate (761.7 mg, 6.7 mmol) was added at room temperature. Thisreaction solution was heated at 70° C. in nitrogen stream for 3 hoursand then poured into a liquid mixture of ethyl acetate with water. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous sodium sulfate, and concentrated in vacuo. The resultingoily residue was subjected to silica gel column chromatography (Wakogel™C-300, 60 ml; ethyl acetate-heptane=4:1) to give (2S,4S)-4-acetylthio-2-hydroxy 4'-(p-nitrobenzyloxycarbonylamino)methyl!-4-biphenyl!methyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidinediastereomer as a pale yellow oily substance (390 mg, yield: 81.8%).

¹H-NMR(CDCl₃)δ:2.10-2.20(1H,m),2.31(3H,s),2.94-3.25(1H,m),3.70-4.31(3H,m),4.44-4.47(2H,m),5.19-5.34(6H,m),7.37-7.62(12H,m),8.20-8.27(4H,m)

REFERENCE EXAMPLE 112

(2S,4S)-4-Actylthio-N-(p-nitrobenzyloxycarbonyl)-2- hydroxy 5-(p-nitrobenzyloxycarbonylamino)methyl!-3-biphenyl!methyl!pyrrolidine##STR316## (Step 1)

(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-(α-hydroxy-3,5-dibromobenzyl)pyrrolidine(19.6 g, yield: 56.9%) was prepared as a yellow oily substance, from(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (20 g, 60.8mmol), 1,3,5-tribromobenzene (19.13 g, 60.8 mmol) and 1.6M n-butyllithium-hexane solution (49.4 ml, 79.04 mmol), in the same manner as inReference Example 111-1.

¹H-NMR(CDCl₃)δ:0.03(6H,s),0.86(9H,s),1.53(9H,s),1.63-2.14(2H,m),2.88-3.64(2H,m),3.92-4.58(2H,m),4.82-5.50(1H,m),7.56(3H,m)

(Step 2)

(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-(5-bromo-3-biphenyl)hydroxymethyl!pyrrolidine (5.9 g, yield: 30.0%) wasprepared from the compound (19.6 g, 34.6 mmol) obtained in Step 1,phenyl borate (2.11 g, 17.3 mmol),tetrakistriphenylphosphinepalladium(0) (1.2 g, 1.04 mmol) and sodiumcarbonate (3.3 g, 31.2 mmol), in the same manner as Reference Example111-2.

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.84(9H,s),1.51(9H,s),1.85(2H,m),2.71-3.61(2H,m),3.80-4.60(2H,m),4.81-5.49(1H,m),7.49(8H,m)

(Step 3)

To a solution of the compound (5.7 g, 10.4 mmol) obtained in Step 2 intetrahydrofuran (30 ml), a solution of 1.6M n-butyl lithium-hexanesolution (19 ml, 30.4 mmol) in tetrahydrofuran was added dropwise at-78° C. in a nitrogen stream over 30 minutes. This reaction solution wasstirred at the same temperature for 30 minutes and thendimethylformamide (5 ml) was added dropwise thereto over 1 minute. Thereaction solution was poured into a liquid mixture of ethyl acetate withwater. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, and concentrated invacuo. The resulting oily residue was subjected to silica gel columnchromatography (Wakogel™ C-300, heptane-ethyl acetate=5:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(5-formyl-3-biphenyl)hydroxymethyl!pyrrolidine (1.16 g, 22.3%) as a paleyellow oily substance.

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.81(9H,s),1.51(9H,s),1.82(1H,m),2.74-3.94(3H,m),4.08-4.73(2H,m),5.01-5.58(1H,m),7.46(3H,m),7.61(2H,m),7.84(2H,m),8.02(1H,m),10.09(1H,s)

(Step 4)

To a solution of the compound (1.15 g, 2.25 mmol) obtained in Step 3 intetrahydrofuran, sodium boron hydride (128 mg, 3.37 mmol) was addedunder cooling with ice and this reaction solution was stirred at roomtemperature for 30 minutes. The reaction solution was poured into aliquid mixture of ethyl acetate with water. The organic layer was washedwith saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate, and concentrated in vacuo to give a crude product of(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-hydroxy(5-hydroxymethyl-3-biphenyl)methyl!pyrrolidine (1.02 g) as ayellow oily substance, which was used for the next reaction withoutpurification.

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.81(9H,s),1.52(9H,s),1.83(1H,m),2.86-3.59(2H,m),3.81-4.80(5H,m),4.92-5.32(1H,m),7.19-7.64(8H,m)

(Step 5)

To a solution of the compound (1.01 g, 1.97 mmol) obtained in Step 4 indichloromethane (20 ml), triethylamine (330 μl, 2.36 mmol) and mesylchloride (152 μl, 1.97 mmol) were successively added in a nitrogenstream under cooling with ice and this reaction solution was stirred atthe same temperature for 10 minutes. The reaction solution was pouredinto a liquid mixture of ethyl acetate with water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and concentrated in vacuo to give a crude product of(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-hydroxy(5-mesyloxy-3-biphenyl)methyl!pyrrolidine as a yellow oilysubstance, which was used for the next reaction without purification.

(Step 6)

A crude product of (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(5-azidomethyl-3-biphenyl)hydroxymethyl!pyrrolidine was prepared as ayellow oily substance from the compound obtained in Step 5 and sodiumazide (384 mg, 5.91 mmol), in the same manner as in Reference Example111-7. The crude product was used for the next reaction withoutpurification.

(Step 7)

(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2- hydroxy 5-(p-nitrobenzyloxycarbonylamino)methyl!-3-biphenyl!methyl!pyrrolidine(1.06 g, yield: 78.1%) was prepared as a white oily substance from thecompound obtained in Step 6, triphenylphosphine (1.03 g, 3.94 mmol) andp-nitrobenzyloxycarbonyl chloride (552 mg, 2.56 mmol), in the samemanner as in Reference Example 111-8.

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.80(9H,s),1.40(9H,s),1.80(1H,m),2.84-4.31(5H,m),4.42(2H,m),4.84-5.36(3H,m),7.40(10H,m),8.21(2H,m)

(Step 8)

A solution of the compound (1.05 g, 1.52 mmol) obtained in Step 7 in2.6N hydrogen chloride-methanol was stirred at room temperature for 20minutes. This reaction solution was concentrated in vacuo to give acrude product of (2S,4R)-4-hydroxy-2- hydroxy 5-(p-nitrobenzyloxycarbonylamino)methyl!-3-biphenyl!methyl!pyrrolidine asa yellow oily substance, which was used for the next reaction withoutpurification.

(Step 9)

A solution of the crude product obtained in Step 8 in dioxane-water(5:1, 30 ml) was adjusted to pH 10.0 with 1N aqueous sodium hydroxide.To this solution, a solution of p-nitrobenzyloxycarbonyl chloride (426mg, 1.96 mmol) in dioxane (2 ml) was added dropwise, while the reactionsolution was maintained at pH 8.0-10.0 by using 1N aqueous sodiumhydroxide. The reaction solution was poured into a liquid mixture ofethyl acetate with water. The organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The resulting oily residue was subjected tosilica gel column chromatography (Wakogel™ C-300, heptane-ethylacetate=1:3) to give (2S,4R)-2- hydroxy 5-(p-nitrobenzyloxycarbonylamino)methyl!-3-biphenyl!methyl!-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(718 mg, yield: 72.0%) as a colorless oily substance.

¹H-NMR(CDCl₃)δ:1.77(1H,m),3.10-3.80(2H,m),4.16-4.51(4H,m),4.63(1H,m),5.26(4H,m),5.88(1H,m),7.36(12H,m),8.21(4H,m)

(Step 10)

A crude product of (2S,4R)-2- hydroxy 5-(p-nitrobenzyloxycarbonylamino)methyl!-3-biphenyl!methyl!-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidinewas prepared as a yellow oily substance from the compound (703 mg, 1.07mmol) obtained in Step 9, triethylamine (178.4 μl, 1.28 mmol) and mesylchloride (83 μl, 1.07 mmol), in the same manner as in Reference Example112-5. The crude product was used for the next reaction withoutpurification.

(Step 11)

The title compound (218 mg, yield: 28.3%) was prepared as a brown oilysubstance from the crude product obtained in Step 1 and potassiumthioacetate (367 mg, 3.21 mmol), in the same manner as in ReferenceExample 111-10.

¹ H-NMR(CDCl₃)δ:2.01(1H,m),2.30(3H,s),3.12(1H,m),3.72(1H,m),4.21(2H,m),4.41(2H,m),5.26(5H,m),5.78(1H,m),7.40(12H,m),8.21(4H,m)

REFERENCE EXAMPLE 113

(2S,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-hydroxy(2-naphthyl)methyl!pyrrolidine ##STR317## (Step 1)

Magnesium (3.4 g) and a solution of 1,2-dibromoethane (5.3 ml, 60.8mmol) in diethyl ether (40 ml) were successively added to a solution of2-bromonaphthalene (12.6 g, 60.8 mmol) in diethyl ether (160 ml) at roomtemperature in a nitrogen stream and this reaction solution was refluxedunder heating for 2.5 hours. The reaction solution was gradually cooledand a solution of(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (10 g, 30.4mmol) in tetrahydrofuran (50 ml) was added dropwise thereto undercooling with ice. Then, the reaction solution was stirred at roomtemperature for 1 hour. After addition of water, the reaction solutionwas concentrated in vacuo and was poured into a liquid mixture of ethylacetate with water. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, and concentratedin vacuo. The resulting oily residue was subjected to silica gel columnchromatography (Wakogel™ C-300, heptane-ethyl acetate=4:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-hydroxy(2-naphthyl)methyl!pyrrolidine (9.38 g, yield: 67.5%) as a yellowoily substance.

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.76(9H,s),1.51(9H,s),1.86(1H,m),2.83(1H,m),3.28(1H,m),3.46-3.84(1H,m),4.03-4.44(1H,m),4.46-4.73(1H,m),5.01-5.43(1H,m),7.46(3H,m),7.80(4H,_(m))

(Step 2)

A crude product of (2S,4R)-4-hydroxy-2-hydroxy(2-naphthyl)methyl!pyrrolidine monohydrochloride was prepared asa pale red powder from the compound (2.17 g, 4.74 mmol) obtained in Step1 and 2N hydrogen chloride-dioxane solution (50 ml), in the same manneras in Reference Example 112-8. The crude product was used for the nextreaction without purification.

¹ H-NMR(D₂ O)δ:1.71-2.03(1H,m),2.04-2.31(1H,m),3.33(1H,m),3.54(1H,m),4.39(1H,m),4.62(1H,m),4.99-5.40(1H,m), 7.62(3H,m),7.98(4H,m)

(Step 3)

(2S,4R)-4-hydroxy-2-hydroxy(2-naphthyl)methyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (1.68g, yield: 84.0%) was prepared as a white solid from the crude productobtained in Step 2 and p-nitrobenzyloxycarbonyl chloride (1.33 g, 6.16mmol), in the same manner as in Reference Example 112-9.

¹H-NMR(CDCl₃)δ:1.51-1.96(1H,m),2.11-2.42(1H,m),3.18-3.68(2H,m),4.28-4.61(2H,m),4.98-5.47(3H,m),7.51(5H,m),7.80(4H,m),8.26(2H,m)

(Step 4)

A crude product of (2S,4R)-2-hydroxy(2-naphthyl)methyl!-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(1.57 g) was prepared as a brown powder from the compound (1.68 g, 3.98mmol) obtained in Step 3, triethylamine (555 μl, 3.98 mmol) and mesylchloride (308 μl, 3.98 mmol), in the same manner as in Reference Example112-5. The crude product was used for the next reaction withoutpurification.

¹ H-NMR(CDCl₃)δ:1.91(1H,m),2.42(1H,m),2.96(3H,s),3.03(1H,m),3.60(1H,m),4.02(1H,m),4.46(1H,m),5.16-5.53(3H,m),7.51(5H,m),7.83(4H,m),8.26(2H,m)

(Step 5)

The title compound (615 mg, yield: 32.2%) was prepared from the crudeproduct (1.57 g, 3.98 mmol) obtained in Step 4 and potassium thioacetate(1.36 g, 11.9 mmol), in the same manner as in Reference Example 111-10.

¹ H-NMR(CDCl₃)δ:2.02(2H,m),2.31(3H,s),2.91-3.37(1H,m),3.75(1H,m),4.04-4.41(2H,m),4.83-5.52(3H,m),7.46(5H,m),7.80(4H,m),8.23(2H,m)

REFERENCE EXAMPLE 114

(2S,4S)-4-Acetylthio-N-(p-nitrobenzyloxycarbonyl)-2- hydroxy 4-(p-nitrobenzyloxycarbonylamino)methyl!-1-naphthyl!methyl!pyrrolidinediastereomer I ##STR318## (Step 1)

(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-hydroxy(4-hydroxymethyl-1-naphthyl)methyl!pyrrolidine (2.71 g, yield:44.0%) was prepared as a colorless oily substance from(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (4.17 g,12.7 mmol), 4-hydroxymethyl-1-bromonaphthalene (3 g, 12.7 mmol) and 1.6Mn-butyl lithium-hexane solution (20.6 ml, 39.9 mmol), in the same manneras in Reference Example 111-1.

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.79(9H,s),1.54(9H,s),2.01(2H,m),3.26-3.52(2H,m),4.03-4.68(2H,m),5.03-5.36(2H,m),5.94-6.29(1H,m),7.52(4H,m),8.09(1H,m),8.38(1H,m)

(Step 2)

A crude product of (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-hydroxy(4-mesyloxymethyl-1-naphthyl)methyl!pyrrolidine was prepared as ayellow oily substance from the compound (1.56 g, 3.20 mmol) obtained inStep 1, triethylamine (535 μl, 3.84 mmol) and mesyl chloride (248 μl,3.20 mmol), in the same manner as in Reference Example 112-5. The crudeproduct was used for the next reaction without purification.

(Step 3)

A crude product of (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-hydroxy(4-azidomethyl-1-naphthyl)methyl!pyrrolidine was prepared as ayellow oily substance from the crude product obtained in Step 2 andsodium azide (624 mg, 9.6 mmol), in the same manner as in ReferenceExample 111-7. This crude product was used for the next reaction withoutpurification.

(Step 4)

(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2- hydroxy 4-(p-nitrobenzyloxycarbonylamino)methyl!-1-naphthyl!methyl!pyrrolidine(570 mg) was prepared as a yellow oily substance from the compoundobtained in Step 3 and p-nitrobenzyloxycarbonyl chloride (897 mg, 4.16mmol), in the same manner as in Reference Example 111-9.

¹ H-NMR(CDCl₃)δ:1.40(1H,m),2.03(1H,m),3.19-3.72(2H,m),4.12(1H,m),4.43(1H,m),4.82(2H,m),5.23(2H,m),6.00(1H,m),7.51(6H,m),7.92-8.43(4H,m)

(Step 5)

A crude product of (2S,4R)-4-hydroxy-2- hydroxy 4-(p-nitrobenzyloxycarbonylamino)methyl!-1-naphthyl!methyl!pyrrolidine wasprepared as a yellow oily substance from the compound (570 mg, 0.857mmol) obtained in Step 4 and 2.7N hydrogen chloride-methanol solution(20 ml), in the same manner as in Reference Example 112-8. This crudeproduct was used for the next reaction without purification.

(Step 6)

(2S,4R)-4-Hydroxy-2- hydroxy 4-(p-nitrobenzyloxycarbonylamino)methyl!-1-naphthyl!methyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidinediastereomer I (265 mg, yield: 49.1%) and diastereomer II (86 mg, yield:15.9%) were prepared as colorless oily substances from the crude productobtained in Step 5 and p-nitrobenzyloxycarbonyl chloride (240 mg, 1.11mmol), in the same manner as in Reference Example 112-9.

Diastereomer I

¹ H-NMR(CDCl₃)δ:1.38(1H,m),2.33(2H,m),3.68(2H,m),4.50(2H,m),4.82(2H,m),5.12-5.48(4H,m),7.38-7.69(8H,m),8.00(1H,m),8.21(4H,m),8.50(1H,m)

Diastereomer II

¹ H-NMR(CDCl₃)δ:1.44(1H,m),2.38(1H,m),3.50(1H,m),3.73(1H,m),4.21(1H,m),4.70(3H,m),5.27(4H,m),5.96(1H,m),7.54(8H,m),7.96(1H,m),8.22(4H,m), 8.40(1H,m)

(Step 7)

A crude product of (2S,4R)-2- hydroxy 4-(p-nitrobenzyloxycarbonylamino)methyl!-1-naphthyl!methyl!-4-mesyloxy-N-(p-nitrobenzyloxycarbonyl)pyrrolidinediastereomer I was prepared as a yellow oily substance from the compound(diastereomer I, 265 mg, 0.42 mmol) obtained in Step 6, triethylamine(70 μl, 0.51 mmol) and mesyl chloride (33 μl, 0.42 mmol) in the samemanner as in Reference Example 112-5, and used for the next reactionwithout purification.

(Step 8)

The title compound (127 mg, yield: 43.9%) was prepared as a yellow oilysubstance from the compound obtained in Step 7 and potassium thioacetate(114 mg, 1.26 mmol) in the same manner as in Reference Example 111-10.

¹ H-NMR(CDCl₃)δ:1.72(1H,m),2.13(1H,m),2.31(3H,s),3.28(1H,m),3.71(2H,m),4.25(1H,m),4.38(1H,m),4.83(2H,m),5.13-5.42(4H,m),7.36-7.72(8H,m),8.02(1H,m),8.22(4H,m),8.42(1H,m

REFERENCE EXAMPLE 115

(2S,4S)-4-Acetylthio-2- α-hydroxy-3-(D-nitrobenzyloxycarbonylamino)methyl!benzyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidinediastereomers A and B ##STR319## (Step 1)

A solution of 3-(tetrahydropyranyloxymethyl)bromobenzene (11.8 g, 43.5mmol) in tetrahydrofuran (20 ml) was added dropwise to a solution of1.6M n-butyl lithium-hexane solution (30 ml, 48 mmol) in tetrahydrofuran(100 ml) at -78° C. in a nitrogen stream over 15 minutes. This reactionsolution was stirred at -78° C. for 40 minutes and then a solution of(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (7.2 g,21.9 mmol) in tetrahydrofuran (20 ml) was added dropwise over 20minutes. The reaction solution was stirred at -78° C. for 30 minutes andthen allowed to gradually warm and saturated aqueous ammonium chloridewas added thereto. This solution was poured into a liquid mixture ofethyl acetate with water and the organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The resulting oily residue was subjected tosilica gel column chromatography (Wakogel™ C-300, heptane-ethylacetate=6:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-α-hydroxy-3-(tetrahydropyranyloxymethyl)benzyl!pyrrolidine (6.3 g,yield: 55.0%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ:0.02(6H,s),0.82(9H,s),1.38-2.00(17H,m),3.19-3.98(5H,m),4.08-4.56(4H,m),4.62-5.17(3H,m)

(Step 2)

To a solution of the compound (6.3 g, 12.1 mmol) obtained in Step 1 inmethanol (270 ml), pyridinium p-toluenesulfonate (275 mg, 1.09 mmol) wasadded at room temperature in a nitrogen stream and this reactionsolution was stirred at 55° C. for 5 hours. The reaction solution waspoured into a liquid mixture of ethyl acetate-water. The organic layerwas washed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and concentrated in vacuo. The resulting residue wassubjected to silica gel column chromatography (Wakogel™ C-300,heptane-ethyl acetate=1:2) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-α-hydroxy-3-hydroxymethylbenzyl!pyrrolidine (2.0 g, yield: 35.5%) as apale yellow oily substance.

¹ H-NMR(CDCl₃)δ:0.03(6H,s),0.85(9H,s),1.38-1.92(11H,m),2.86-3.93(3H,m),4.09-4.62(2H,m),4.73(2H,s),4.90-5.28(1H,m),6.10-6.20(1H,m),7.21-7.53(4H,m)

(Step 3)

To a solution of the compound (2.0 g, 4.58 mmol) obtained in Step 2 intetrahydrofuran (20 ml), triethylamine (700 μl, 5.02 mmol)and mesylchloride (390 μl, 5.04 mmol) were successively added in a nitrogenstream under cooling with ice and this reaction solution was stirred atthe same temperature for 20 minutes. This solution was poured into aliquid mixture of ethyl acetate with water water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate and concentrated in vacuo to give a crude product of(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-α-hydroxy-3-(mesyloxymethyl)benzyl!pyrrolidine as a pale yellow oilysubstance, which was used for the next reaction without purification.

¹ H-NMR(CDCl₃)δ:0.03(6H,s),0.84(9H,s),1.42-1.68(10H,m),1.78-1.91(1H,m),2.95(3H,s),3.26-3.95(3H,m),4.10-4.76(2H,m),4.92-5.31(2H,m),6.21-6.30(1H,m),7.31-7.48(4H,m)

(Step 4)

To a solution of the compound obtained in Step 3 inN,N-dimethylformamide (20 ml), sodium azide (360 mg, 5.54 mmol) wasadded at room temperature in a nitrogen stream and this reactionsolution was stirred at 70° C. for 2 hours. The reaction solution waspoured into a liquid mixture of ethyl acetate with water. The organiclayer was washed with saturated aqueous sodium chloride, dried overanhydrous sodium sulfate, and concentrated in vacuo. The resultingresidue was subjected to silica gel column chromatography (Wakogel™C-300, heptane-ethyl acetate=10:1) to give(2S,4R)-2-(3-azidomethyl-α-hydroxybenzyl)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)pyrrolidine(2.0 g, yield: 94.5%) as a yellow oily substance.

¹ H-NMR(CDCl₃)δ:0.01(6H,s),0.82(9H,s),1.48-1.90(11H,m),2.80-3.89(3H,m),4.04-4.60(4H,m),7.20-7.42(4H,m)

(Step 5)

To a solution of the compound (2.5 g, 5.41 mmol) obtained in Step 4 intetrahydrofuran (25 ml), water (200 μl, 11.1 mmol) andtriphenylphosphine (1.8 g, 6.86 mmol) were successively added at roomtemperature in a nitrogen stream and this reaction solution was stirredat the same temperature for 15 hours. The reaction solution wasconcentrated in vacuo to give a yellow oily residue. A solution of theresidue in 2.17N hydrogen chloride-methanol (19 ml) was stirred at roomtemperature for 4 hours. This reaction solution was concentrated invacuo and dichloromethane was added to the resulting residue. Thevolatile components were distilled off in vacuo to give an oily residue(4.2 g). A solution of the residue in dioxane-water (1:1, 40 ml)adjusted to pH 9.0 with 1N aqueous sodium hydroxide. To this solution, asolution of p-nitrobenzyloxycarbonyl chloride (2.4 g, 11.9 mmol) indioxane (5 ml) was added dropwise at room temperature, while thereaction solution was maintained at pH 8.0-9.0 by using 1N aqueoussodium hydroxide. The reaction solution was poured into a liquid mixtureof ethyl acetate-water. The organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The resulting residue was subjected to silica gelcolumn chromatography (Wakogel™ C-300, heptane-ethyl acetate=1:4→ethylacetate) to give (2S,4R)-4-hydroxy-2- α-hydroxy-3-(p-nitrobenzyloxycarbonylamino)methyl!benzyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidinediastereomer A as a pale yellow substance (less polar compound, 807 mg,yield: 25.7%) and diastereomer B as a pale yellow oily substance (polarcompound, 978 mg, yield: 31.2%).

Diastereomer A

¹H-NMR(CDCl₃)δ:1.72-1.92(1H,m),2.01-2.20(1H,m),3.28-3.71(2H,m),4.16-4.50(4H,m),5.15-5.32(5H,m),8.12-8.30(4H,m)

Diastereomer B

¹H-NMR(CDCl₃)δ:1.47-1.70(1H,m),1.98-2.20(1H,m),3.37-3.80(2H,m),4.10-4.66(4H,m),5.27(2H,s),5.30(2H,s),5.82(1H,br s),8.12-8.28(4H,m)

(Step 6)

(2S,4S)-4-Acetylthio-2- α-hydroxy-3-(p-nitrobenzyloxycarbonylamino)methyl!benzyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidinediastereomer A (345 mg, yield: 44.3%) and diastereomer B (356 mg, yield:38.0%) were prepared as red oily substances from the diastereomer A (807mg, 1.39 mmol) and the diastereomer B (987 mg, 1.69 mmol) obtained inStep 5, respectively, in the same manners as in Reference Examples112-10 and 112-11.

Diastereomer A

¹H-NMR(CDCl₃)δ:1.89-2.10(1H,m),2.30(3H,s),2.90-3.19(1H,m),3.61-3.80(1H,m),4.08-4.26(2H,m),4.37(2H,d,J=5.9Hz),5.07-5.38(6H,m),7.12-7.31(5H,m),7.41-7.62(3H,m),8.12-8.30(4H,m)

Diastereomer B

¹H-NMR(CDCl₃)δ:1.89-2.06(1H,m),2.32(3H,s),3.16-3.28(1H,m),3.68-3.81(1H,m),4.08-4.31(2H,m),4.40(2H,d,J=6.1Hz),5.09-5.38(5H,m),5.72(1H,br s)

REFERENCE EXAMPLES 116a to 117

The following compounds were prepared in the same manner as in ReferenceExample 115.

    __________________________________________________________________________     ##STR320##                                                                   Ex.                                                                           No.                                                                              R              .sup.1 H-NMR (CDCl.sub.3) δ                                                                 Remarks                                 __________________________________________________________________________    116a                                                                              ##STR321##    2.20-2.27(1H, m), 2.34(3H, s), 3.18-3.30 (1H, m),                             3.62-3.85(1H, m), 4.02-4.63(4H, m), 5.01-5.33(5H, m),                         5.71(1H, br s), 7.20- 7.68(8H, m), 8.10-8.32(4H,                                                  Diastereomer A (less polar)             116b                                                                              ##STR322##    1.30-1.48(1H, m), 2.30(3H, s), 3.18-3.32 (1H, m),                             3.55-3.90(1H, m), 4.02-4.65(3H, m), 4.86(1H, d,                               J=7.6Hz), 5.02-5.32(5H, m), 5.62-5.70(1H, m), 7.22-7.61                       (8H, m), 8.12- 8.30(4H, m)                                                                        Diastereomer B (polar)                  117                                                                               ##STR323##    1.82-2.20(1H, m), 2.31 and 2.32(3H, each s),                                  2.88-3.31(1H, m), 3.58-3.80(1H, m), 4.08-4.30(3H, m),                         4.38(2H, d, J=2.7Hz), 5.10- 5.38(6H, m), 7.19-7.35(4H,                        m), 7.42-7.61 (4H, m), 8.13-8.32(4H, m)                                                           --                                      __________________________________________________________________________

REFERENCE EXAMPLE 118

(2S,4S)-4-Acetylthio-2- (S)-α-hydroxy-4-(p-nitrobenzyloxycarbonylamino)methyl!benzyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidine##STR324## (Step 1)

1.6M n-Butyl lithium-hexane solution (104 ml, 167 mmol) was addeddropwise to a solution of 1-bromo-4-(methoxymethoxymethyl)benzene (38.6g, 167 mmol) in tetrahydrofuran (350 ml) at -78° C. in a nitrogen streamover 30 minutes. This reaction solution was stirred at -78° C. for 30minutes and then a solution of(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (27.5 g,83.5 mmol) in tetrahydrofuran (300 ml) was added dropwise thereto over 1hour. This reaction solution was stirred at -70° C. for 2 hours and thenwarmed and saturated aqueous ammonium chloride was added thereto at -20°C. To the reaction mixture, a liquid mixture of ethyl acetate with waterwas added. The organic layer was washed successively with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate andsaturated aqueous sodium chloride, then dried over anhydrous magnesiumsulfate, and concentrated in vacuo. The resulting oily residue wassubjected to silica gel column chromatography (Wakogel™ C-300,heptane-ethyl acetate=4:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-α-hydroxy-4-(methoxymethoxymethyl)benzyl!pyrrolidine (24.1 g, yield:59.8%) as a colorless oily substance.

¹ H-NMR(CDCl₃)δ:0.00(6H,s),0.85(6H,s),1.50(9H,s),3.40(3H,s),4.57(2H,s),4.70(2H,s),6.02(1H,s), 7.33(4H,br s)

(Step 2)

Oxalyl chloride (7.7 ml, 90 mmol) was added dropwise to a solution ofdimethyl sulfoxide (12 ml, 170 mmol) in methylene chloride (300 ml) at-78° C. over 15 minutes and the resulting solution was stirred at thesame temperature for 30 minutes. To this reaction solution, a solutionof the compound (24.1 g, 50 mmol) obtained in Step 1 in methylenechloride (250 ml) was added dropwise at -70° C. over 30 minutes. Thereaction solution was stirred at the same temperature for 30 minutes.After dropwise addition of triethylamine (48 ml, 350 mmol) at -70° C.,the reaction solution was allowed to warm and water (300 ml) was addedthereto at 0° C. The organic layer was washed successively with water,dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate andsaturated aqueous sodium chloride, and dried over anhydrous magnesiumsulfate. The solvent was distilled off in vacuo to give a crude productof (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-4-(methoxymethoxymethyl)benzoyl!pyrrolidine (25 g).

¹ H-NMR(CDCl₃)δ:0.08(6H,s),0.90(9H,s),1.25(5H,s),1.47(4H,s),1.98(1H,m),2.23(1H,m),3.43(3H,s),3.66-3.82(1H,m),4.43(1H,m),4.66(2H,s),4.73(2H,s),5.26-5.48(1H,m),7.45(1H,d,J=8.3Hz),7.48(1H,d,J=8.3Hz),7.92(1H,d,J=8.3Hz),7.95(1H,d,J=8.3Hz)

(Step 3)

To a solution of the compound (10.08 g, 21 mmol) obtained in Step 2 intetrahydrofuran (200 mg), 1.0M L-Selectride™-tetrahydrofuran (32.7 ml,32.7 mmol) was added at -78° C. This reaction solution was stirred atthe same temperature for 4 hours and then warmed. To the reactionsolution, saturated aqueous ammonium chloride was added at -20° C. andthen a liquid mixture of ethyl acetate with water was added. The organiclayer was washed successively with dilute hydrochloric acid, saturatedaqueous sodium hydrogencarbonate and saturated aqueous sodium chloride,and dried over anhydrous sodium sulfate. The solvent was distilled offin vacuo to give a crude product of(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-α-hydroxy-4-(methoxymethoxymethyl)benzyl!pyrrolidine (13.0 g) as acolorless oily substance.

¹ H-NMR(CDCl₃)δ:0.00(6H,s),9.85(6H,s),1.49(9H,s),3.40(3H,s),4.57(2H,s),4.70(2H,s),6.02(1H,s), 7.33(4H,br s)

(Step 4)

To a solution of the compound (13.0 g) obtained in Step 3 in pyridine(100 ml), acetic anhydride (20 ml) and 4-N,N-dimethylaminopyridine (800mg, 6.5 mmol) were added. This reaction solution was stirred at roomtemperature overnight and then the solvent was distilled off in vacuo.To the resulting residue, ethyl acetate and 3N hydrochloric acid wereadded. The organic layer was washed successively with dilutehydrochloric acid, water and saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, and concentrated in vacuo. Theresulting oily substance was subjected to silica gel columnchromatography (Lobar™ LiChroprep™ Si60, heptane-ethyl acetate=4:1) togive (2S,4R)-2-(S)-α-acetoxy-4-(methoxymethoxymethyl)benzyl!-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)pyrrolidine(less polar compound, 5.11 g, yield: 46%) as a colorless oily substance.

¹ H-NMR(CDCl₃)δ:-0.08(6H,br s),0.80(9H,br s), 1.58(9H,br s),2.14(3H,brs),3.42(3H,s),4.59(2H,s), 4.71(2H,s),7.20-7.41(4H,m)

(Step 5)

To a solution of the compound (4.81 g, 9.18 mmol) obtained in Step 4 inmethanol (40 ml), aqueous potassium carbonate (30 ml) (4.0 g, 28.9 mmol)was added at room temperature. To this reaction mixture, methanol (40ml) was added. This reaction solution was stirred at room temperaturefor 40 minutes and then concentrated in vacuo. The residue was extractedwith ethyl acetate. The organic layer was washed successively with waterand saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and concentrated in vacuo. The resulting oily substance wassubjected to silica gel column chromatography (Wakogel™ C-300,heptane-ethyl acetate=4:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(S)-α-hydroxy-4-(methoxymethoxymethyl)benzyl!pyrrolidine (4.3 g, yield:97%).

¹ H-NMR(CDCl₃)δ:0.05(6H,s),0.87(9H,s),1.56(9H,s),3.36(1H,m),3.46(3H,s),3.57(1H,m),4.13(1H,m),4.29(1H,m),4.58(1H,m),4.64(2H,s),4.76(2H,s), 6.07(1H,br s),7.39(4H,br s)

(Step 6)

To a solution of the compound (1.72 g, 3.57 mmol) obtained in Step 5 inmethanol (40 ml), 2N hydrogen chloride-methanol solution (20 ml) wasadded. After stirring at room temperature overnight, this reactionsolution was concentrated in vacuo to give (2S,4R)-4-hydroxy-2-(S)-α-hydroxy-4-(hydroxymethyl)benzyl!pyrrolidine monohydrochloride as asolid residue, which was used for the next step without purification.

(Step 7)

A solution of the residue obtained in Step 6 in dioxane (50 ml) andwater (30 ml) was brought to pH 10.0 by adding 1N aqueous sodiumhydroxide. To this solution, a solution of p-nitrobenzyloxycarbonylchloride (856 mg, 4.0 mmol) in dioxane (30 ml) was added dropwise undercooling with ice, while the reaction solution was maintained at pH9.0-10.0 by using 1N aqueous sodium hydroxide. This reaction solutionwas poured into a liquid mixture of ethyl acetate-water. The organiclayer was washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, and concentrated in vacuo. The resultingresidue was subjected to silica gel column chromatography (Wakogel™C-300, heptane-ethyl acetate=1:1→ethyl acetate) to give(2S,4R)-4-hydroxy-2-(S)-α-hydroxy-4-(hydroxymethyl)benzyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(1.11 g, yield: 77%).

¹ H-NMR(CDCl₃)δ:3.44(1H,m),3.71(1H,m),4.21(1H,m),4.37(1H,m),4.62(1H,m),4.68(2H,s),5.30(2H,s), 5.57(1H,br s),7.32(4H,brs),7.54(2H,d,J=8.8Hz), 8.24(2H,d,J=8.8Hz)

(Step 8)

To a solution of the compound (990 mg, 2.46 mmol) obtained in Step 7 inmethylene chloride (15 ml)--acetone (5 ml), p-toluenesulfonyl chloride(495 mg, 2.6 mmol) and triethylamine (0.36 ml, 2.6 mmol) were added at0° C. This reaction solution was stirred at 5° C. for 2 days and thenconcentrated in vacuo and a liquid mixture of ethyl acetate with waterwas added to the resulting residue. The organic layer was washedsuccessively with dilute hydrochloric acid, water and saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, andconcentrated in vacuo. The resulting oily substance was subjected tosilica gel column chromatography (Wakogel™ C-300, heptane-ethylacetate=1:1→1:4) to give (2S,4R)-4-hydroxy-2-(S)-α-hydroxy-4-(p-toluenesulfonyloxymethyl)benzyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(362 mg, yield: 26%).

¹ H-NMR(CDCl₃)δ:2.08(3H,s),4.51(2H,s),5.32(2H,s), 7.35(4H,brs),7.57(2H,d,J=8.0Hz),8.26(2H,d,J=8.0Hz)

(Step 9)

To a solution of the compound obtained in Step 8 in dimethyl sulfoxide(5 ml), sodium azide (143 mg, 2.2 mmol) was added. This reactionsolution was stirred at 60° C. for 15 minutes, then cooled in an icebath, and poured into a liquid mixture of ethyl acetate with water. Theorganic layer was washed successively with water and saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, andconcentrated in vacuo to give a crude product of (2S,4R)-4-hydroxy-2-(S)-α-hydroxy-4-(azidomethyl)benzyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(300 mg).

¹ H-NMR(CDCl₃)δ:3.47(1H,m),3.76(1H,m),4.25(1H,m),4.35(2H,s),4.70(1H,m),5.33(2H,s),5.62(1H,brs),7.34(4H,m),7.57(2H,d,J=8.8Hz),8.27(2H,d,J=8.8Hz)

(Step 10)

To a solution of the compound (300 mg) obtained in Step 9 intetrahydrofuran (5 ml), triphenylphosphine (275 mg, 1.05 mmol) and water(40 μl, 2.1 mmol) were added at room temperature and this reactionsolution was stirred at the same temperature overnight. To the reactionmixture, triethylamine (0.18 ml, 1.3 mmol) and p-nitrobenzyloxycarbonylchloride (153 mg, 0.71 mmol) were added at room temperature. Thereaction solution was stirred at the same temperature for 30 minutes andthen concentrated. A liquid mixture of ethyl acetate with water wasadded thereto. The organic layer was washed successively with water andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and concentrated in vacuo. The resulting residue was subjected to silicagel column chromatography (Wakogel™ C-300, heptane-ethylacetate=1:2→ethyl acetate) to give (2S,4R)-4-hydroxy-2- (S)-α-hydroxy-4-(p-nitrobenzyloxycarbonylamino)methyl!benzyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(328 mg, yield: 87%).

¹ H-NMR(CDCl₃)δ:3.45(1H,m),3.74(1H,m),4.23(1H,m),4.37(2H,d,J=5.9Hz),4.62(1H,m),5.23(2H,s),5.30(2H,s),5.65(1H,m),7.27(4H,m), 7.53(4H,d,J=8.0Hz),8.22(4H,d,J=8.0Hz)

(Step 11)

(2S,4S)-4-Acetylthio-2- (S)-α-hydroxy-4-(p-nitrobenzyloxycarbonylamino)methyl!benzyl!-N-(p-nitrobenzyloxycarbonyl)pyrrolidine(110 mg, yield: 29%) was prepared from the compound (325 mg, 0.57 mmol)obtained in Step 10, in the same manners as in Reference Examples 112-10and 112-11.

¹ H-NMR(CDCl₃)δ:2.01(1H,m),2.32(3H,s),3.22(1H,m),3.76(1H,m),4.21(2H,m),4.38(2H,d,J=6.0Hz),4.70(1H,m),5.15(1H,m),5.23(2H,s),5.28(2H,d,J=2.7Hz),5.62(1H,m),7.20-7.35(4H,m),7.53(4H,d,J=8.0Hz),8.23(4H,d,J=8.6Hz)

REFERENCE EXAMPLE 119

(2S,4S)-4-Acetylthio-2-(α-hydroxybenzyl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine##STR325## (Step 1)

2.0M Phenylmagnesium bromide-tetrahydrofuran solution (22.8 ml, 45.6mmol) was added dropwise to a solution of(2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (10 g, 30.4mmol) in tetrahydrofuran (200 ml) at -78° C. in a nitrogen stream over15 minutes. This reaction solution was gradually warmed and stirred atroom temperature for 3 hours. After addition of water, the reactionsolution was concentrated in vacuo. The resulting residue was pouredinto a liquid mixture of ethyl acetate with water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and concentrated in vacuo. The resulting oily residuewas subjected to silica gel column chromatography (Wakogel™ C-300,heptane-ethyl acetate=4:1) to give(2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(α-hydroxybenzyl)pyrrolidine(12.0 g, yield: 96.8%) as a colorless oily substance.

¹H-NMR(CDCl₃)δ:0.01(6H,s),0.83(9H,s),1.54(9H,s),1.79-1.92(1H,m),2.83-3.84(3H,m),4.08-4.61(2H,m),4.84-5.34(1H,m)

(Steps 2 and 3)

(2S,4S)-4-Acetylthio-2-(α-hydroxybenzyl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidinewas prepared in the same manners as in Reference Examples 112-8, 112-10and 112-11.

¹H-NMR(CDCl₃)δ:1.86(1H,m),2.32(3H,s),2.71(1H,m),3.38-3.39(1H,m),4.01-4.33(2H,m),4.66-4.83(1H,m),5.13-5.37(3H,m),7.32(5H,m),7.54(2H,m),8.26(2H,m)

In the following Reference Example 120, physicochemical data of acompound used in Examples as a thiol or a thiol derivative are shown.

REFERENCE EXAMPLE 120 ##STR326##

¹ H-NMR(CDCl₃)δ:1.52(1H,m),2.05(1H,m),2.31(3H,s),3.22(1H,m),3.75(1H,m),4.17(1H,m),4.20-4.40(3H,m),4.55-4.70(4H,m),5.01(1H,brd,J=8Hz),5.10-5.40(4H,m),5.85-6.15(2H,m),6.98(1H,t,J=8.5Hz),7.20(1H,m),7.42(1H,m)

INDUSTRIAL APPLICABILITY

The compounds of the present invention are novel compounds not disclosedin any literatures and are useful as antibacterial agents by virtue oftheir strong antibacterial activities against gram positive bacterialincluding MRSA and against gram negative bacteria and their excellentstability against β-lactamase and against DHP-I. Particularly, they areexpected to make a great contribution to treatment for hardly curableinfectious deceases caused by MRSA.

We claim:
 1. A compound of the formula: ##STR327## wherein R¹ is ahydrogen atom or a lower alkyl group, R² is a hydrogen atom or anegative charge, R³ is a hydrogen atom or a lower alkyl group, Ar is aphenyl group, a naphthyl group or a group of: ##STR328## (wherein eachof A₄ and A₅, which may be the same or different, is a single bond, amethylene group, an ethylene group, an oxygen atom, an imino group, asulfur atom, a sulfonyl group, --CONH-- or --NHSO₂ --, and Het is apyrrolinyl group, a pyrrolyl group, an imidazolyl group, an imidazoliogroup, a pyrazolyl group, a thiazolyl group, a pyridyl group, apyridinio group, a pyrazinyl group, a quinolyl group, an isoquinolylgroup, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, amorpholinyl group, a benzothiazolyl group, an isoindolyl group, aquinuclidinyl group, a quinuclidinio group, abenzothiazol-1,1-dioxo-6-yl group or a 1,4-diazabicyclo 2.2.2!octanylgroup which may be substituted with the same or different one to threesubstituents, selected from the group consisting of a hydroxyl group, ahalogen atom, a cyano group, a carboxyl group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a di-loweralkylcarbamoyl group, a carbamoyloxy group, an amino group, a loweralkylamino group, a di-lower alkylamino group, a tri-lower alkylammoniogroup, a formimidoylamino group, an acetimidoylamino group, a loweralkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, asulfo group, a sulfamoyl group, a lower alkylsulfamoyl group, a di-loweralkylsulfamoyl group, a lower alkyl group, a hydroxy lower alkyl groupand a carbamoyl lower alkyl group) which may be substituted with thesame or different one to five substituents selected from the groupconsisting of a lower alkyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a lower alkylamino group, a lower alkoxygroup, an aryloxy group, a lower alkylthio group, a lower alkylsulfonylgroup and a lower alkylsulfamoyl group which may be substituted with thesame or different one to three substituents selected from the groupconsisting of a hydroxyl group, a halogen atom, a cyano group, acarboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a loweralkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxygroup, an amino group, a lower alkylamino group, a di-lower alkylaminogroup, a tri-lower alkylammonio group, a carbamoyl lower alkylaminogroup, an aroylamino group, an amino lower alkyl group, an amino loweralkylcarbonyl amino group, a pyridyl group, a pyridylcarbonylaminogroup, a pyridiniocarbonylamino group, a formimidoylamino group, anacetimidoylamino group, a lower alkoxy group, a lower alkylthio group, asulfo group, an aminosulfonyl group, a lower alkylsulfonyl group and adi-lower alkylsulfonyl group, and a hydroxyl group, a halogen atom, acyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoylgroup, a di-lower alkylcarbamoyl group, an arylcarbamoyl group, apiperazinocarbonyl group, an amino group, a di-lower alkylamino group, atri-lower alkylammonio group, a sulfamino group, a lower alkanoylaminogroup, an aralkylamino group, an aroylamino group, an arylsulfonylaminogroup, an amino lower alkylcarbonylamino group, a sulfamoyl group and adi-lower alkylsulfamoyl group, each of A₁, A₂ and A₃, which may be sameor different, is a single bond or a lower alkylene group which may besubstituted with a substituent selected from the group consisting of alower alkyl group, a lower alkylcarbamoyl group, a lower alkylaminogroup, a lower alkoxy group, a lower alkylthio group, a loweralkylsulfonyl group, a lower alkylsulfonylamino group and a loweralkylsulfamoyl group which may be substituted with the same or differentone to three substituents selected from the group consisting of ahydroxyl group, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino group, alower alkylamino group, a di-lower alkylamino group, a tri-loweralkylammonio group, a formimidoylamino group, an acetimidoylamino group,a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonylgroup, a sulfo group, a sulfamoyl group, a lower alkylsulfamoyl groupand a di-lower alkylsulfamoyl group, and a pyridyl group and a pyridiniogroup (wherein the pyridyl group and the pyridinio group may besubstituted with a substituent selected from the group consisting of alower alkyl group, a carboxy lower alkyl group and a carbamoyl loweralkyl group), and W is a sulfur atom, a group of N-X (wherein X is ahydrogen atom, a lower alkyl group, a formyl group, a lower alkanoylgroup or a sulfamoyl group), an oxygen atom, a group of CH(OH) or asingle bond; or a pharmaceutically acceptable salt or ester thereof. 2.The compound according to claim 1, wherein W is a sulfur atom; or apharmaceutically acceptable salt or ester thereof.
 3. The compoundaccording to claim 1, wherein W is a group of N-X (wherein X is ahydrogen atom, a lower alkyl group, a formyl group, a lower alkanoylgroup or a sulfamoyl group), an oxygen atom, a group of CH(OH) or asingle bond; or a pharmaceutically acceptable salt or ester thereof. 4.The compound according to claim 3, wherein W is a group of N-X (whereinX is a hydrogen atom, a lower alkyl group, a formyl group, a loweralkanoyl group or a sulfamoyl group); or a pharmaceutically acceptablesalt or ester thereof.
 5. The compound according to claim 3, wherein Wis an oxygen atom; or a pharmaceutically acceptable salt or esterthereof.
 6. The compound according to claim 3, wherein W is a group ofCH(OH); or a pharmaceutically acceptable salt or ester thereof.
 7. Thecompound according to claim 3, wherein W is a single bond; or apharmaceutically acceptable salt or ester thereof.
 8. The compoundaccording to claim 1, which is represented by the formula: ##STR329##wherein R^(1a) is a lower alkyl group, R^(2a) is a hydrogen atom or anegative charge, R^(3a) is a hydrogen atom, Ar_(a) is a phenyl group, anaphthyl group or a group of: ##STR330## (wherein each of A_(4a) andA_(5a), which may be the same or different, is a single bond, amethylene group or an ethylene group, and Het^(a) is an imidazoliogroup, a pyridinio group, a morpholinyl group, a quinuclidinio group ora 1,4-diazabicyclo 2.2.2!octanyl group which may be substituted with thesame or different one to three substituents selected from the groupconsisting of a lower alkyl group, a hydroxy lower alkyl group and acarbamoyl lower alkyl group) which may be substituted with the same ordifferent one to five substituents selected from the group consisting ofa lower alkyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a lower alkylamino group, a lower alkoxygroup, a lower alkylthio group, a lower alkylsulfonyl group and a loweralkylsulfamoyl group which may be substituted with the same or differentone to three substituents selected from the group consisting of ahydroxyl group, a carboxyl group, a carbamoyl group, an amino group anda lower alkylamino group, and a hydroxyl group, a halogen atom, acarboxyl group, a carbamoyl group, an amino group and a sulfamoyl group,each of A_(1a), A_(2a) and A_(3a), which may be the same or different,is a single bond or a lower alkylene group which may be substituted witha substituent selected from the group consisting of a lower alkyl group,a lower alkylcarbamoyl group, a lower alkylamino group, a lower alkoxygroup, a lower alkylthio group, a lower alkylsulfonyl group, a loweralkylsulfonylamino group and a lower alkylsulfamoyl group which may besubstituted with the same or different one to three substituentsselected from the group consisting of a hydroxyl group, a carbamoylgroup, an amino group, a lower alkylamino group and a lower alkylthiogroup, and a pyridyl group and a pyridinio group (wherein the pyridylgroup and the pyridinio group may be substituted with a substituentselected from the group consisting of a lower alkyl group, a carboxylower alkyl group and a carbamoyl lower alkyl group), and W_(a) is asulfur atom, a group of N-X_(a) (wherein X_(a) is a hydrogen atom, alower alkyl group, a formyl group, a lower alkanoyl group or a sulfamoylgroup), an oxygen atom, a group of CH(OH) or a single bond; or apharmaceutical acceptable salt or ester thereof.
 9. The compoundaccording to claim 8, wherein W_(a) is a sulfur atom; or apharmaceutically acceptable salt or ester thereof.
 10. The compoundaccording to claim 8, wherein W_(a) is a group of N-X_(a) (wherein X_(a)is a hydrogen atom, a lower alkyl group, a formyl group, a loweralkanoyl group or a sulfamoyl group), an oxygen atom, a group of CH(OH)or a single bond; or a pharmaceutically acceptable salt or esterthereof.
 11. The compound according to claim 10, wherein W_(a) is agroup of N-X_(a) (wherein X_(a) is a hydrogen atom, a lower alkyl group,a formyl group, a lower alkanoyl group or a sulfamoyl group); or apharmaceutically acceptable salt or ester thereof.
 12. The compoundaccording to claim 10, wherein W_(a) is an oxygen atom; or apharmaceutically acceptable salt or ester thereof.
 13. The compoundaccording to claim 10, wherein W_(a) is a group of CH(OH); or apharmaceutically acceptable salt or ester thereof.
 14. The compoundaccording to claim 10, wherein W_(a) is a single bond; or apharmaceutically acceptable salt or ester thereof.
 15. The compoundaccording to claim 8, which is represented by the formula: ##STR331##wherein R^(1b) is a lower alkyl group, R^(2b) is a hydrogen atom or anegative charge, R^(3b) is a hydrogen atom, Ar_(b) is a phenyl group, anaphthyl group or a group of: ##STR332## (wherein each of A_(4b) andA_(5b), which may be the same or different, is a single bond, amethylene group or an ethylene group, and Het^(b) is an imidazolio groupor a 1,4-diazabicyclo 2,2,2!octanyl group which may be substituted withthe same or different one to three substituents selected from the groupconsisting of a hydroxy lower alkyl group and a carbamoyl lower alkylgroup) which may be substituted with the same or different one to fivesubstituents selected from the group consisting of a lower alkyl group,a lower alkylcarbamoyl group, a lower alkylsulfonylamino group, a loweralkylthio group, a lower alkylsulfonyl group and a lower alkylsulfamoylgroup which may be substituted with the same or different one to threesubstituents selected from the group consisting of an amino group and alower alkylamino group, and a halogen atom, a carbamoyl group and asulfamoyl group, each of A_(1b), A_(2b) and A_(3b), which may be thesame or different, is a single bond or a lower alkylene group which maybe substituted with a substituent selected from the group consisting ofa lower alkyl group which may be substituted with the same or differentone to three substituents selected from the group consisting of acarbamoyl group, an amino group and a lower alkylamino group, and apyridyl group and a pyridinio group (wherein the pyridyl group and thepyridinio group may be substituted with a substituent selected from thegroup consisting of a lower alkyl group, a carboxy lower alkyl group anda carbamoyl lower alkyl group), and W_(b) is a sulfur atom, a group ofN-X_(b) (wherein X_(b) is a hydrogen atom, a lower alkyl group, a formylgroup, a lower alkanoyl group or a sulfamoyl group), an oxygen atom, agroup of CH(OH) or a single bond; or a pharmaceutical acceptable salt orester thereof.
 16. The compound according to claim 15, wherein W_(b) isa sulfur atom; or a pharmaceutically acceptable salt or ester thereof.17. The compound according to claim 15, wherein W_(b) is a group ofN-X_(b) (wherein X_(b) is a hydrogen atom, a lower alkyl group, a formylgroup, a lower alkanoyl group or a sulfamoyl group), an oxygen atom, agroup of CH(OH) or a single bond; or a pharmaceutically acceptable saltor ester thereof.
 18. The compound according to claim 17, wherein W_(b)is a group of N-X_(b) (wherein X_(b) is a hydrogen atom, a lower alkylgroup, a formyl group, a lower alkanoyl group or a sulfamoyl group); ora pharmaceutically acceptable salt or ester thereof.
 19. The compoundaccording to claim 17, wherein W_(b) is an oxygen atom; or apharmaceutically acceptable salt or ester thereof.
 20. The compoundaccording to claim 17, wherein W_(b) is a group of CH(OH); or apharmaceutically acceptable salt or ester thereof.
 21. The compoundaccording to claim 17, wherein W_(b) is a single bond; or apharmaceutically acceptable salt or ester thereof.
 22. The compoundaccording to claim 1, which is represented by the formula: ##STR333##wherein R^(1c) is a hydrogen atom or a lower alkyl group, R^(2c) is ahydrogen atom or a negative charge, R^(3c) is a hydrogen atom or a loweralkyl group, Ar_(c) is a phenyl group, a naphthyl group or a group of:##STR334## (wherein each of A_(4c) and A_(5c), which may be the same ordifferent, is a single bond, a methylene group, an oxygen atom, an iminogroup, a sulfur atom, a sulfonyl group, --CONH-- or --NHSO₂ --, andHet^(c) is a pyrrolinyl group, a pyrrolyl group, an imidazolyl group, animidazolio group, a pyrazolyl group, a thiazolyl group, a pyridyl group,a pyridinio group, a pyrazinyl group, a quinolyl group, an isoquinolylgroup, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, amorpholinyl group, a benzothiazolyl group, an isoindolyl group, aquinuclidinyl group, a quinuclidinio group, abenzothiazol-1,1-dioxo-6-yl group or a 1,4-diazabicyclo 2.2.2!octanylgroup which may be substituted with the same or different one to threesubstituents selected from the group consisting of a hydroxyl group, ahalogen atom, a cyano group, a carboxyl group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a di-loweralkylcarbamoyl group, a carbamoyloxy group, an amino group, a loweralkylamino group, a di-lower alkylamino group, a tri-lower alkylammoniogroup, a formimidoylamino group, an acetimidoylamino group, a loweralkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, asulfo group, a sulfamoyl group, a lower alkylsulfamoyl group and adi-lower alkylsulfamoyl group) which may be substituted with the same ordifferent one to five substituents selected from the group consisting ofa lower alkyl group, a lower alkylcarbamoyl group, a lower alkylaminogroup, a lower alkoxy group, an aryloxy group, a lower alkylthio group,a lower alkylsulfonyl group and a lower alkylsulfamoyl group which maybe substituted with the same or different one to three substituentsselected from the group consisting of a hydroxyl group, a halogen atom,a cyano group, a carboxyl group, a lower alkoxycarbonyl group, acarbamoyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoylgroup, a carbamoyloxy group, an amino group, a lower alkylamino group, adi-lower alkylamino group, a tri-lower alkylammonio group, a carbamoyllower alkylamino group, an aroylamino group, an amino lower alkyl group,an amino lower alkylcarbonylamino group, a pyridyl group, apyridylcarbonylamino group, a pyridiniocarbonylamino group, aformimidoylamino group, an acetimidoylamino group, a lower alkoxy group,a lower alkylthio group, a sulfo group, an aminosulfonyl group, a loweralkylsulfonyl group and a di-lower alkylsulfonyl group, and a hydroxylgroup, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a di-lower alkylcarbamoylgroup, an arylcarbamoyl group, a piperazinocarbonyl group, an aminogroup, a di-lower alkylamino group, a tri-lower alkylammonio group, asulfamino group, a lower alkanoylamino group, an aralkylamino group, anaroylamino group, an arylsulfonylamino group, an amino loweralkylcarbonylamino group, a sulfamoyl group and a di-loweralkylsulfamoyl group, each of A_(1c), A_(2c) and A_(3c), which may besame or different, is a single bond or a lower alkylene group which maybe substituted with a substituent selected from the group consisting ofa lower alkyl group, a lower alkylcarbamoyl group, a lower alkylaminogroup, a lower alkoxy group, a lower alkylthio group, a loweralkylsulfonyl group, a lower alkylsulfonylamino group and a loweralkylsulfamoyl group which may be substituted with the same or differentone to three substituents selected from the group consisting of ahydroxyl group, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino group, alower alkylamino group, a di-lower alkylamino group, a tri-loweralkylammonio group, a formimidoylamino group, an acetimidoylamino group,a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonylgroup, a sulfo group, a sulfamoyl group, a lower alkylsulfamoyl groupand a di-lower alkylsulfamoyl group, and a pyridyl group (wherein thepyridyl group may be substituted with a substituent selected from thegroup consisting of a lower alkyl group, a carboxy lower alkyl group anda carbamoyl lower alkyl group), and W_(c) is a sulfur atom; or apharmaceutically acceptable salt or ester thereof.
 23. The compoundaccording to claim 1, which is represented by the formula: ##STR335##wherein R^(1d) is a hydrogen atom or a lower alkyl group, R^(2d) is ahydrogen atom, R^(3d) is a hydrogen atom or a lower alkyl group, each ofR^(4d) and R^(5d), which may be the same or different, is a hydrogenatom, a halogen atom, a hydroxyl group, a carbamoyl group or a sulfamoylgroup, X_(d) is a hydrogen atom, a lower alkyl group, a formyl group ora lower alkanoyl group, either either Y_(d) or Z_(d) is a hydrogen atom,the other is a group (d): ##STR336## (wherein each of R^(6d) and R^(7d),which may be the same or different, is a hydrogen atom or a lower alkylgroup, or R^(6d) and R^(7d) form a C₂₋₆ alkylene group, and P_(d) is aninteger of from 0 to 3), each of A_(d) and B_(d), which may be the sameor different, is a phenyl group or a naphthyl group (provided thatR^(5d), B_(d) and Z_(d) may form a hydrogen atom), m_(d) is 1 or 2, andn_(d) is 0 or 1 (provided that when Y_(d) or Z_(d) is a hydrogen atom,Z_(d) and R^(5d), or Y_(d) and R^(4d) may form a nitrogen-containing 5to 7-membered heterocyclic ring); or a pharmaceutically acceptable saltor ester thereof.
 24. The compound according to claim 1, which isrepresented by the formula: ##STR337## wherein R^(1e) is a hydrogen atomor a lower alkyl group, R^(2e) is a hydrogen atom, R^(3e) is a hydrogenatom or a lower alkyl group, each of R^(4e) and R^(5e), which may be thesame or different, is a hydrogen atom, a carbamoyl group or a sulfamoylgroup, either Y_(e) or Z_(e) is a hydrogen atom, the other is a group(e): ##STR338## (wherein each of R^(6e) and R^(7e), which may be thesame or different, is a hydrogen atom or a lower alkyl group, or R^(6e)and R^(7e) form a C₂₋₆ alkylene group, and p_(e) is an integer of from 0to 3), each of A_(e) and B_(e), which may be the same or different, is aphenyl group or a naphthyl group (provided that R^(5e), B_(e) and Z_(e)may form a hydrogen atom), m_(e) is 1 or 2, and n_(e) is 0 or 1(provided that when Y_(e) or Z_(e) is a hydrogen atom, Z_(e) and R^(5e),or Y_(e) and R^(4e) may form a nitrogen-containing 5 to 7-memberedheterocyclic ring); or a pharmaceutically acceptable salt or esterthereof.
 25. The compound according to claim 1, which is represented bythe formula: ##STR339## wherein R^(1f) is a hydrogen atom or a loweralkyl group, R^(2f) is a hydrogen atom, R^(3f) is a hydrogen atom, alower alkyl group or a lower alkenyl group, each of R^(4f) and R^(5f),which may be the same or different, is a hydrogen atom, a halogen atom,a hydroxyl group, a lower alkyl group, a carbamoyl group or a sulfamoylgroup, either Y_(f) or Z_(f) is a hydrogen atom, the other is a group(f): ##STR340## (wherein each of R^(6f) and R^(7f), which may be thesame or different, is a hydrogen atom or a lower alkyl group, or R^(6f)and R^(7f) form a C₂₋₆ alkylene group, and p_(f) is an integer of from 0to 3), each of A_(f) and B_(f), which may be the same or different, is aphenyl group or a naphthyl group (provided that R^(5f), B_(f) and Z_(f)may form a hydrogen atom), and n_(f) is an integer of from 1 to 3(provided that when Y_(f) or Z_(f) is a hydrogen atom, Z_(f) and R^(5f),or Y_(f) and R^(4f) may form a nitrogen-containing 5 to 7-memberedheterocyclic ring); or a pharmaceutically acceptable salt or esterthereof.
 26. The compound according to claim 1, which is represented bythe formula: ##STR341## wherein R^(1g) is a hydrogen atom or a loweralkyl group, R^(2g) is a hydrogen atom, R^(3g) is a hydrogen atom or alower alkyl group, each of R^(4g) and R^(5g), which may be the same ordifferent, is a hydrogen atom, a halogen atom, a hydroxyl group, a loweralkyl group, a carbamoyl group or a sulfamoyl group, either Y_(g) orZ_(g) is a hydrogen atom, the other is a group (g): ##STR342## (whereineach of R^(6g) and R^(7g), which may be the same or different, is ahydrogen atom or a lower alkyl group, or R^(6g) and R^(7g) may form aC₂₋₆ alkylene group, and p_(g) is an integer of from 0 to 3), R^(8g) isa hydrogen atom, each of A_(g) and B_(g), which may be the same ordifferent, is a phenyl group or a naphthyl group (provided that R^(5g),B_(g) and Z_(g) may form a hydrogen atom), mg is an integer of 1 or 2,and n_(g) is an integer of 0 or 1 (provided that when Y_(g) or Z_(g) isa hydrogen atom, Z_(g) and R^(5g), or Y_(g) and R^(4g) may form anitrogen-containing 5 to 7-membered heterocyclic ring); or apharmaceutically acceptable salt or ester thereof.
 27. The compoundaccording to claim 1, which is:(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylthio)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-(3-aminomethyl-4-chlorophenyl)thiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethyl-2-sulfamoylphenyl)thiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylcarbamoyl)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylcarbamoyl)-2-sulfamoylphenyl!thiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethyloxy)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-(3-aminopropionylamino)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylsulfonylamino)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-aminomethylphenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylsulfamoyl)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2-(3S,5S)-5-(8-aminomethyl-2-naphthylmethylthiomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2-(3S,5S)-5-(3-aminomethyl-5-glycylamino-2-naphthylmethylthiomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-(3-aminoethylsulfonylaminoethyl)-2-naphthylmethylthiomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2-(3S,5S)-5-(3-aminomethyl-5-glycylaminomethyl-2-naphthylmethylthiomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5- 6-(4-carbamoylmethyl-l,4-diazabicyclo2.2.2!octanedium-1-ylmethyl)-2-naphthylmethylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5- 3-(4-carbamoylmethyl-1,4-diazabicyclo2.2.2!octanedium-1-ylmethyl)-2-naphthylmethylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethylphenylaminomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethyl-1-naphthylaminomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethylphenoxymethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethylphenylethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethylbenzyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethyl-1-naphthylmethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethylphenyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethyl-5-phenylphenyl)hydroxymethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethyl-1-naphthylmethyl)hydroxymethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethylphenyl)hydroxymethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid or(1R,5S,6S)-2- (3S,5S)-5-(5-aminomethyl-2-fluorophenyl)hydroxymethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid;or apharmaceutically acceptable salt or ester thereof.
 28. The compoundaccording to claim 1, which is:(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylthio)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-aminomethyl-2-sulfamoylphenyl)thiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylcarbamoyl)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylcarbamoyl)-2-sulfamoylphenyl!thiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-(3-aminopropionylamino)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylsulfonylamino)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-aminomethylphenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-4-(2-aminoethylsulfamoyl)phenylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2-(3S,5S)-5-(8-aminomethyl-2-naphthylmethylthiomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5- 6-(4-carbamoylmethyl-1,4-diazobicyclo2.2.2!octanedium-1-ylmethyl)-2-naphthylmethylthiomethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethylphenylaminomethyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethylbenzyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid,(1R,5S,6S)-2- (3S,5S)-5-(4-aminomethylphenyl)pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid or(1R,5S,6S)-2-(3S,5S)-5-(4-aminomethylphenyl)hydroxymethyl!pyrrolidin-3-ylthio!-6-(1R)-hydroxyethyl!-1-methyl-1-carbapen-2-em-3-carboxylic acid; or apharmaceutically acceptable salt or ester thereof.
 29. A process forproducing a compound of the formula: ##STR343## wherein R¹ is a hydrogenatom or a lower alkyl group, R² is a hydrogen atom or a negative charge,R³ is a hydrogen atom or a lower alkyl group, Ar is a phenyl group, anaphthyl group or a group of: ##STR344## (wherein each of A₄ and A₅,which may be the same or different, is a single bond, a methylene group,an ethylene group, an oxygen atom, an imino group, a sulfur atom, asulfonyl group, --CONH-- or --NHSO₂ --, and Het is a pyrrolinyl group, apyrrolyl group, an imidazolyl group, an imidazolio group, a pyrazolylgroup, a thiazolyl group, a pyridyl group, a pyridinio group, apyrazinyl group, a quinolyl group, an isoquinolyl group, a pyrrolidinylgroup, a piperidyl group, a piperazinyl group, a morpholinyl group, abenzothiazolyl group, an isoindolyl group, a quinuclidinyl group, aquinuclidinio group, a benzothiazol-1,1-dioxo-6-yl group or a1,4-diazabicyclo 2.2.2!octanyl group which may be substituted with thesame or different one to three substituents, selected from the groupconsisting of a hydroxyl group, a halogen atom, a cyano group, acarboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a loweralkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxygroup, an amino group, a lower alkylamino group, a di-lower alkylaminogroup, a tri-lower alkylammonio group, a formimidoylamino group, anacetimidoylamino group, a lower alkoxy group, a lower alkylthio group, alower alkylsulfonyl group, a sulfo group, a sulfamoyl group, a loweralkylsulfamoyl group, a di-lower alkylsulfamoyl group, a lower alkylgroup, a hydroxy lower alkyl group and a carbamoyl lower alkyl group)which may be substituted with the same or different one to fivesubstituents selected from the group consisting of a lower alkyl group,a lower alkylcarbamoyl group, a lower alkylsulfonylamino group, a loweralkylamino group, a lower alkoxy group, an aryloxy group, a loweralkylthio group, a lower alkylsulfonyl group and a lower alkylsulfamoylgroup which may be substituted with the same or different one to threesubstituents selected from the group consisting of a hydroxyl group, ahalogen atom, a cyano group, a carboxyl group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a di-loweralkylcarbamoyl group, a carbamoyloxy group, an amino group, a loweralkylamino group, a di-lower alkylamino group, a tri-lower alkylammoniogroup, a carbamoyl lower alkylamino group, an aroylamino group, an aminolower alkyl group, an amino lower alkylcarbonylamino group, a pyridylgroup, a pyridylcarbonylamino group, a pyridiniocarbonylamino group, aformimidoylamino group, an acetimidoylamino group, a lower alkoxy group,a lower alkylthio group, a sulfo group, an aminosulfonyl group, a loweralkylsulfonyl group and a di-lower alkylsulfonyl group, and a hydroxylgroup, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a di-lower alkylcarbamoylgroup, an arylcarbamoyl group, a piperazinocarbonyl group, an aminogroup, a di-lower alkylamino group, a tri-lower alkylammonio group, asulfamino group, a lower alkanoylamino group, an aralkylamino group, anaroylamino group, an arylsulfonylamino group, an amino loweralkylcarbonylamino group, a sulfamoyl group and a di-loweralkylsulfamoyl group, each of A₁, A₂ and A₃, which may be same ordifferent, is a single bond or a lower alkylene group which may besubstituted with a substituent selected from the group consisting of alower alkyl group, a lower alkylcarbamoyl group, a lower alkylaminogroup, a lower alkoxy group, a lower alkylthio group, a loweralkylsulfonyl group, a lower alkylsulfonylamino group and a loweralkylsulfamoyl group which may be substituted with the same or differentone to three substituents selected from the group consisting of ahydroxyl group, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino group, alower alkylamino group, a di-lower alkylamino group, a tri-loweralkylammonio group, a formimidoylamino group, an acetimidoylamino group,a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonylgroup, a sulfo group, a sulfamoyl group, a lower alkylsulfamoyl groupand a di-lower alkylsulfamoyl group, and a pyridyl group and a pyridiniogroup (wherein the pyridyl group and the pyridinio group may besubstituted with a substituent selected from the group consisting of alower alkyl group, a carboxy lower alkyl group and a carbamoyl loweralkyl group), and W is a sulfur atom, a group of N-X (wherein X is ahydrogen atom, a lower alkyl group, a formyl group, a lower alkanoylgroup or a sulfamoyl group), an oxygen atom, a group of CH(OH) or asingle bond; or a pharmaceutically acceptable salt or ester thereof,which comprises reacting a compound of the formula: ##STR345## whereinR¹ is as defined above, R¹⁰ is a hydrogen atom or a hydroxyl-protectinggroup, and R²⁰ is a hydrogen atom or a carboxyl-protecting group, or areactive derivative thereof, with a compound of the formula: ##STR346##wherein R³⁰ is a hydrogen atom, a lower alkyl group or animino-protecting group, Ar₀ is a phenyl group, a naphthyl group or agroup of: ##STR347## (wherein each of A₄₀ and A₅₀, which may be the sameor different, is a single bond, a methylene group, an ethylene group, anoxygen atom, an imino group which may be protected, a sulfur atom, asulfonyl group, --CONH-- or --NHSO₂ --, and Het⁰ is a pyrrolinyl group,a pyrrolyl group, an imidazolyl group, an imidazolio group, a pyrazolylgroup, a thiazolyl group, a pyridyl group, a pyridinio group, apyrazinyl group, a quinolyl group, an isoquinolyl group, a pyrrolidinylgroup, a piperidyl group, piperazinyl group, a morpholinyl group, abenzothiazolyl group, an isoindolyl group, a quinuclidinyl group, aquinuclidinio group, a benzthiazol-1,1-dioxo-6-yl group or a1,4-diazabicyclo 2.2.2!octanyl group which may be substituted with thesame or different one to three substituents selected from the groupconsisting of a hydroxyl group which may be protected, a halogen atom, acyano group, a carboxyl group which may be protected, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino groupwhich may be protected, a lower alkylamino group, a di-lower alkylaminogroup, a tri-lower alkylammonio group, a formimidoylamino group, anacetimidoylamino group, a lower alkoxy group, a lower alkylthio group, alower alkylsulfonyl group, a sulfo group, a sulfamoyl group, a loweralkylsulfamoyl group, a di-lower alkylsulfamoyl group, a lower alkylgroup, a hydroxy lower alkyl group which may be protected and acarbamoyl lower alkyl group) which may be substituted with the same ordifferent one to five substituents selected from the group consisting ofa lower alkyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a lower alkylamino group, a lower alkoxygroup, an aryloxy group, a lower alkylthio group, a lower alkylsulfonylgroup and a lower alkylsulfamoyl group which may be substituted with thesame or different one to three substituents selected from the groupconsisting of a hydroxyl group which may be protected, a halogen atom, acyano group, a carboxyl group which may be protected, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino groupwhich may be protected, a lower alkylamino group, a di-lower alkylaminogroup, a tri-lower alkylammonio group, a carbamoyl lower alkylaminogroup, an aroylamino group, an amino lower alkyl group which may beprotected, an amino lower alkylcarbonylamino group which may beprotected, a pyridyl group, a pyridylcarbonylamino group, apyridiniocarbonylamino group, a formimidoylamino group, anacetimidoylamino group, a lower alkoxy group, a lower alkylthio group, asulfo group, an aminosulfonyl group, a lower alkylsulfonyl group and adi-lower alkylsulfonyl group, and a hydroxyl group which may beprotected, a halogen atom, a cyano group, a carboxyl group which may beprotected, a lower alkoxycarbonyl group, a carbamoyl group, a di-loweralkylcarbamoyl group, an arylcarbamoyl group, a piperazinocarbonylgroup, an amino group which may be protected, a di-lower alkylaminogroup, a tri-lower alkylammonio group, a sulfamino group, a loweralkanoylamino group, an aralkylamino group, an aroylamino group, anarylsulfonylamino group, an amino lower alkylcarbonylamino group whichmay be protected, a sulfamoyl group and a di-lower alkylsulfamoyl group,each of A₁₀, A₂₀ and A₃₀, which may be the same or different, is asingle bond or a lower alkylene group which may be substituted with asubstituent selected from the group consisting a lower alkyl group, alower alkylcarbamoyl group, a lower alkylamino group, a lower alkoxygroup, a lower alkylthio group, a lower alkylsulfonyl group, a loweralkylsulfonylamino group and a lower alkylsulfamoyl group which may besubstituted with the same or different one to three substituentsselected from the group consisting of a hydroxy group which may beprotected, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino groupwhich may be protected, a lower alkylamino group, a di-lower alkylaminogroup, a tri-lower alkylammonio group, a formimidoylamino group, anacetimidoylamino group, a lower alkoxy group, a lower alkylthio group, alower alkylsulfonyl group, a sulfo group, a sulfamoyl group, a loweralkylsulfamoyl group and a di-lower alkylsulfamoyl group, and a pyridylgroup and pyridinio group (wherein the pyridyl group and the pyridiniogroup may be substituted with a substituent selected from the groupconsisting of a lower alkyl group, a carboxy lower alkyl group which maybe protected and a carbamoyl lower alkyl group), and W₀ is a sulfuratom, a group of N-X₀ (wherein X₀ is a hydrogen atom, anamino-protecting group, a lower alkyl group, a formyl group, a loweralkanoyl group or a sulfamoyl group), an oxygen atom, a group of CH(OR⁸)(wherein R⁸ is a hydrogen atom or a hydroxyl-protecting group) or asingle bond, to obtain a compound of the formula: ##STR348## wherein R¹,R⁵, R²⁰, R³⁰, A₁₀, A₂₀, A₃₀, Ar₀ and W₀ are as defined above, then ifnecessary, removing any protecting groups of the compound of the formulaIV!, and if necessary, converting the compound thus obtained into apharmaceutically acceptable salt or non-toxic ester thereof.
 30. Anantibacterial agent containing, as an active ingredient, a compound ofthe formula: ##STR349## wherein R¹ is a hydrogen atom or a lower alkylgroup, R² is a hydrogen atom or a negative charge, R³ is a hydrogen atomor a lower alkyl group, Ar is a phenyl group, a naphthyl group or agroup of: ##STR350## (wherein each of A₄ and A₅, which may be the sameor different, is a single bond, a methylene group, an ethylene group, anoxygen atom, an imino group, a sulfur atom, a sulfonyl group, --CONH--or --NHSO₂ --, and Het is a pyrrolinyl group, a pyrrolyl group, animidazolyl group, an imidazolio group, a pyrazolyl group, a thiazolylgroup, a pyridyl group, a pyridinio group, a pyrazinyl group, a quinolylgroup, an isoquinolyl group, a pyrrolidinyl group, a piperidyl group, apiperazinyl group, a morpholinyl group, a benzothiazolyl group, anisoindolyl group, a quinuclidinyl group, a quinuclidinio group, abenzothiazol-1,1-dioxo-6-yl group or a 1,4-diazabicyclo 2.2.2!octanylgroup which may be substituted with the same or different one to threesubstituents, selected from the group consisting of a hydroxyl group, ahalogen atom, a cyano group, a carboxyl group, a lower alkoxycarbonylgroup, a carbamoyl group, a lower alkylcarbamoyl group, a di-loweralkylcarbamoyl group, a carbamoyloxy group, an amino group, a loweralkylamino group, a di-lower alkylamino group, a tri-lower alkylammoniogroup, a formimidoylamino group, an acetimidoylamino group, a loweralkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, asulfo group, a sulfamoyl group, a lower alkylsulfamoyl group, a di-loweralkylsulfamoyl group, a lower alkyl group, a hydroxy lower alkyl groupand a carbamoyl lower alkyl group) which may be substituted with thesame or different one to five substituents selected from the groupconsisting of a lower alkyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a lower alkylamino group, a lower alkoxygroup, an aryloxy group, a lower alkylthio group, a lower alkylsulfonylgroup and a lower alkylsulfamoyl group which may be substituted with thesame or different one to three substituents selected from the groupconsisting of a hydroxyl group, a halogen atom, a cyano group, acarboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a loweralkylcarbamoyl group, a di-lower alkylcarbamoyl group, a carbamoyloxygroup, an amino group, a lower alkylamino group, a di-lower alkylaminogroup, a tri-lower alkylammonio group, a carbamoyl lower alkylaminogroup, an aroylamino group, an amino lower alkyl group, an amino loweralkylcarbonylamino group, a pyridyl group, a pyridylcarbonylamino group,a pyridiniocarbonylamino group, a formimidoylamino group, anacetimidoylamino group, a lower alkoxy group, a lower alkylthio group, asulfo group, an aminosulfonyl group, a lower alkylsulfonyl group and adi-lower alkylsulfonyl group, and a hydroxyl group, a halogen atom, acyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoylgroup, a di-lower alkylcarbamoyl group, an arylcarbamoyl group, apiperazinocarbonyl group, an amino group, a di-lower alkylamino group, atri-lower alkylammonio group, a sulfamino group, a lower alkanoylaminogroup, an aralkylamino group, an aroylamino group, an arylsulfonylaminogroup, an amino lower alkylcarbonylamino group, a sulfamoyl group and adi-lower alkylsulfamoyl group, each of A₁, A₂ and A₃, which may be sameor different, is a single bond or a lower alkylene group which may besubstituted with a substituent selected from the group consisting of alower alkyl group, a lower alkylcarbamoyl group, a lower alkylaminogroup, a lower alkoxy group, a lower alkylthio group, a loweralkylsulfonyl group, a lower alkylsulfonylamino group and a loweralkylsulfamoyl group which may be substituted with the same or differentone to three substituents selected from the group consisting of ahydroxyl group, a halogen atom, a cyano group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, adi-lower alkylcarbamoyl group, a carbamoyloxy group, an amino group, alower alkylamino group, a di-lower alkylamino group, a tri-loweralkylammonio group, a formimidoylamino group, an acetimidoylamino group,a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonylgroup, a sulfo group, a sulfamoyl group, a lower alkylsulfamoyl groupand a di-lower alkylsulfamoyl group, and a pyridyl group and a pyridiniogroup (wherein the pyridyl group and the pyridinio group may besubstituted with a substituent selected from the group consisting of alower alkyl group, a carboxy lower alkyl group and a carbamoyl loweralkyl group), and W is a sulfur atom, a group of N-X (wherein X is ahydrogen atom, a lower alkyl group, a formyl group, a lower alkanoylgroup or a sulfamoyl group), an oxygen atom, a group of CH(OH) or asingle bond; or a pharmaceutically acceptable salt or ester thereof.